Insights into the medicinal chemistry of heterocycles integrated with a pyrazolo[1,5-a]pyrimidine scaffold

Mohamed M Hammouda; Hatem E Gaffer; Khaled M Elattar

doi:10.1039/d2md00192f

. 2022 Sep 8;13(10):1150–1196. doi: 10.1039/d2md00192f

Insights into the medicinal chemistry of heterocycles integrated with a pyrazolo[1,5-a]pyrimidine scaffold

Mohamed M Hammouda ^1,², Hatem E Gaffer ³, Khaled M Elattar ^4,^✉

PMCID: PMC9580358 PMID: 36325400

Abstract

Pyrazolo[1,5-a]pyrimidines are the dominant motif of many drugs; for instance, zaleplon and indiplon are sedative agents and ocinaplon was identified as an anxiolytic agent. The importance of this class of compounds lies in its varied and significant biological activities, and accordingly, considerable methods have been devised to prepare these compounds. Hence, other derivatives of this class of compounds were prepared by substitution reactions with different nucleophiles exploiting the activity of groups linked to the ring carbon and nitrogen atoms. The methods used vary through the condensation reactions of the aminopyrazoles with 1,2-allenic, enaminonitriles, enaminones, 1,3-diketones, unsaturated nitriles, or unsaturated ketones. Alternatively, these compounds are prepared through the reactions of acyclic reagents, as these methods were recently developed efficiently with high yields. The current review highlighted the recent progress of the therapeutic potential of pyrazolo[1,5-a]pyrimidines as antimicrobial, anticancer, antianxiety, anti-proliferative, analgesic, and antioxidant agents, carboxylesterase, translocator protein and PDE10A inhibitors, and selective kinase inhibitors.

Pyrazolopyrimidine core is the basic skeleton of many drugs with privileged biological profiles. In this study, the biological characteristics, and samples of synthetic approaches and reactivity of pyrazolo[1,5-a]pyrimidines were highlighted. graphic file with name d2md00192f-ga.jpg

1. Introduction

Heterocyclic pyrazolopyrimidines are a class of [5–6] bicyclic systems with three or four nitrogen atoms resulting in four mainly possible structural isomers. Alternatively, we highlight herein the biological importance and sample synthetic approaches of pyrazolo[1,5-a]pyrimidines; this class of compounds revealed varied and privileged biological significance. Hence, drugs containing a pyrazolo[1,5-a]pyrimidine skeleton obtained synthetically are widely applied; for instance, indiplon (1), lorediplon (2), dorsomorphin (3), zaleplon (4), dinaciclib (5), ocinaplon (6), pyrazophos (7), and anagliptin (8) (Fig. 1),¹ which were used for the treatment of anemia, blocked arteries, and musculoskeletal disorders, possess a great affinity for translocator protein, and are used as sedative and anxiolytic drugs, etc.²

Scientists' interests in recent research are attentive to exploring the diverse and noteworthy biological characteristics of this class of compounds. These heterocyclic compounds have a prodigious impact that stemmed from their potential biological potency as anti-inflammatory, sedative–hypnotic, antitumor, antidiabetic, and anti-fever agents.^3–5 Moreover, these compounds provided potential inhibition for calcium channels in the human body,⁶ besides their activities as antitumor, antimicrobial, antitrichomonal, antischistosomal, anticancer, antitumor, antitrichomonal, anti-inflammatory, antischistosomal, antidepressant, analgesic, antipyretic, and antiviral activities, in addition to sleep disorder treatment.^7–9 Besides, pyrazolo[1,5-a]pyrimidines also revealed privileged biological profiles that were extended by other researchers who reported their antitumor,^10,11 antimycobacterial,¹² antitrypanosomal, and antineuroinflammation activities.¹³ Specifically, pyrazolo[1,5-a]pyrimidines demonstrated potent effects as anxiolytic,^14,15 antischistosomal, xanthine oxidase inhibitor,¹⁶ antimicrobial,^9b,16 tuberculostatic,¹⁷ cytotoxic,^18,19 antiproliferative,²⁰ antileukemic, and antianxiety agents,^21,22 along with their activities as inhibitors against KDR kinase,^23,24 AMP phosphodiesterase,²³ COX-2, and estrogen receptor ligands.²⁵

Additionally, these compounds are also reported as selective inhibitors for Pim-1, HIV-1, CK2,²⁶ HCV polymerase, and c-Src kinase and COX-2-selective for acute ischemic stroke treatment.^27–33 Substituted pyrazolopyrimidines were reported as estrogen receptors, potential competitive antagonists,³⁴ and peripheral benzodiazepine receptors^35,36 and are applied in cancer therapy.³⁷ Furthermore, pyrazolo[1,5-a]pyrimidines were studied as CRF,³⁸ serotonin 5-HT,³⁹ GABA/GABAA,^4,40 and estrogen⁴¹ receptor antagonists, as hepatitis C virus⁴² and COX-2³³ inhibitors, and as potassium channel openers.⁴³ Also, pyrazolo[1,5-a]pyrimidines were applied as PET tumor detection agents,⁴⁴ for drug design,⁴⁵ and as dyes in photographic technology.⁴⁶ Pyrazolopyrimidines were also used to investigate cyanide recognition in water⁴⁷ and are known as selective inhibitors for DDR1.⁴⁸

On the other hand, the chemistry of bicyclic systems and their use in pharmaceutical and medicinal fields attracted researchers' interest in recent years.^49–58 A comprehensive study of the synthetic routes adopted to prepare pyrazolo[1,5-a]pyrimidines has recently been published including all the synthetic courses from aminopyrazoles with different reagents or acyclic reactants under basic or acidic or mild conditions.⁵⁹ Also, other reviews discussed the protocols concerned for the synthesis of pyrazolo[1,5-a]pyrimidines with a non-comprehensive study.^60–62 The anticancer potency and protein kinase inhibitors were reviewed for pyrazolo[1,5-a]pyrimidines by Ismail et al.⁶³ Accordingly, the current review aimed to discuss the constructive and privileged biological potency of a heterocycle-integrated pyrazolo[1,5-a]pyrimidine hybrid that was published in recent years.

2. Model synthetic strategies

Recently, many techniques have been developed to prepare these heterocycles by exploiting the reactivity of aminopyrazole compounds towards numerous active precursors by condensation with 1,2-allenic ketones, enaminonitriles, enaminones, 1,3-dicarbonyl compounds, unsaturated ketones, and many other reagents. Also, many methods have been developed under different catalytic conditions by changing the solvent type (acidic, basic, and neutral medium) or through other eco-friendly protocols or using acyclic reactants. The importance of each method used to synthesize these molecules lies in the ease of obtaining products from readily available reactants with high efficiency, yields, purity, and faster reaction rate.⁵⁹ In particular, pyrazolopyrimidines could be efficiently prepared by condensation reactions of aminopyrazoles with 1,2-allenic ketones,⁶⁴ enaminonitriles, enaminones,^39b,65,66 1,3-dicarbonyl, α,β-unsaturated carbonyl compounds, or ethoxymethylenes,^33,67 β-halovinyl aldehydes under regioselective catalytic conditions,⁶⁸ or 1,3,5-trisubstituted pentane-1,5-diones through C–C bond cleavage with a loss of one carbonyl group⁶⁹ under either microwave or ultrasonic irradiation conditions.^70,71 The compounds of this series might be obtained by three-component reactions⁷² or through two-step processes by condensation of aroyl acetonitriles with hydrazine hydrate⁷³ or sulphonyl hydrazides,⁷⁴ deprived of the isolation of the aminopyrazole compounds. The tremendous biological profile of this class of compounds inspires the researchers to synthesize other molecules with a pyrazolo[1,5-a]pyrimidine nucleus.

2.1. Bicyclic ring construction from β-diketones

Burgart et al.⁷⁵ recently reported the synthesis of two sequences of 6-(2-tolylhydrazono)-dihydropyrazolopyrimidinones 11 and 12 by reactions of β-diketones 9 with aminopyrazoles 10 in toluene at reflux temperature. In this sequence, two possible routes A-1 and B-1 are postulated, in which the exocyclic amino group of aminopyrazoles has two prospects for condensation with carbonyl ketone (route A) or nucleophilic attack at the carbonyl ester (route B) in absence of acid medium that may activate the endocyclic imino group (NH) of the pyrazole ring. Compounds of series 11 have two E- and Z-isomers, in which the Z-isomers are more stable due to the possible six-membered ring construction by hydrogen bond formation of NH-hydrazo with the carbonyl oxygen at the pyrimidine ring (Scheme 1).

Kamal et al.⁷⁶ conveyed the reactions of 1H-pyrazole 10b with β-diketones 13 under catalytic conditions by applying CAN at room temperature to yield the corresponding methyl carboxylates 14. The respective carboxylic acids 15 were attained by basic hydrolysis of the methyl carboxylates 14 (Scheme 2).

Guerrini et al.⁷⁷ reported the synthesis of two series of pyrazolopyrimidinones 19 and 20 by one-step reactions of aminopyrazoles 16 with β-diketones 17 or 18 under solvent-free conditions in diglyme (Scheme 3). Selleri et al.⁷⁸ previously reported the synthesis of 19a, 19e, and 19j of the first series (R₁ = Ph).

Tran et al.⁷⁹ reported the synthesis of bicyclic pyrazolopyrimidines 23 by reactions of the corresponding aminopyrazoles 21 with β-diketones, specifically, acetylacetone (22a: R₂ = Me), and 3,5-heptanedione (22b: R₂ = Et) in ethanol at reflux temperature through cyclocondensation progressions. The cleavage of the isopropyl group was accomplished by reduction with AlCl₃ in CH₂Cl₂ at room temperature to yield the respective phenol analogs 24 (Scheme 4).

The aminopyrazole 25 straightforwardly reacted with β-diketones 26 in acetic acid at reflux temperature to provide the desired bicyclic pyrazolopyrimidines 27–30 in 73–81% yield (Scheme 5). The cyclization step is commonly dependent on the structural characteristics of the diketone and the acid medium, which enable the tautomerization of the amidine system and hence allow the nucleophilic attack of the endocyclic imino group that is more reactive before the nucleophilic attack of the exocyclic amino group at the carbonyl group of the diketone.⁸⁰

2.2. Bicyclic ring construction from α,β-unsaturated ketones

The bicyclic systems pyrazolopyrimidine 33 were proficiently synthesized in 74% yield through the reactions of aminopyrazole 31 with 3-aryl-1-phenylprop-2-en-1-one 32 in ethanol containing piperidine at reflux temperature (Scheme 6), as reported by Fayed et al.⁸⁰ The basic medium enables the condensation of the carbonyl group of the unsaturated ketone with the exocyclic amino group at the first step. In hand, the endocyclic imino group attacks the unsaturated carbon followed by cyclization and auto-oxidation steps. Also, a series of pyrazolopyrimidines 34 were proficiently synthesized in 40–60% yield by Daniels et al.^70c from reactions of 4-aryl-1H-pyrazol-5-amines with 3-hydroxy-2-arylacrylaldehydes under microwave irradiation conditions. In addition, the ethyl carboxylates 35 were obtained with reduced yields (≈35%) from reactions of 4-aryl-1H-pyrazol-5-amines with unsaturated ketones in methanol under reflux conditions.⁴⁵ The reactions of ethyl 5-amino-1H-pyrazole-4-carboxylate with 3-methyl-1-phenylbut-2-en-1-one in DMF/NaH gave the ethyl carboxylates 36.⁸¹ Under conventional or ultrasonic conditions, cyclocondensation of 5-aminopyrazoles with benzylidene acetone in n-butanol gave 4,7-dihydropyrazolo-pyrimidines 37a–c.⁸²

2.3. Bicyclic ring construction from α,β-unsaturated nitriles

Unsaturated nitriles are reactive synthons for the bicyclic ring construction of pyrazolopyrimidines by reactions with aminopyrazole. Hence, Fayed et al.⁸⁰ correspondingly defined the synthetic routes of bicyclic pyrazolopyrimidines 39a and 39b in 63–78% yield by reactions of aminopyrazoles 31 with α,β-unsaturated nitriles 38 in ethanol/piperidine at reflux temperature (Scheme 7). Also, the analogous pyrazolopyrimidines 40a–d⁸³ and carboxamides 41a–f^84,85 were synthesized from the reactions of aminopyrazoles with α,β-unsaturated nitriles under different conditions, predominantly the utility of catalytic piperidine in boiling ethanol.

2.4. Bicyclic ring construction from enaminones

El-Naggar et al.⁸⁶ have synthesized two series of pyrazolo[1,5-a]pyrimidines 44 and 46 in moderate yields by reactions of aminopyrazoles 42 with enaminones 43 and 45, respectively. The acid medium activates the endocyclic imino group of the pyrazole ring to start the first nucleophilic attack; hence the α-carbon of enamine is in a more electrophilic position. Awad⁸⁷ and Askar,⁸⁴ in similar way, reported analogous reactions for anticancer assessment. Guo et al.⁸⁸ reported the synthesis of pyrazolopyrimidines 47 by reactions of the respective aminopyrazoles with enaminones in refluxing acetic acid (Scheme 8).

Kaping's group^89–93 have recently specified the synthesis of pyrazolopyrimidine analogs from the reactions of aminopyrazoles with enaminones or enaminonitriles through facile synthetic routes. Consequently, two series of bicyclic heterocycles 49 and 50 were greenly synthesized through the reactions of enaminones 43 with aminopyrazole 48 catalyzed by potassium bisulfate under ultrasonic irradiation conditions. The reaction of 5-aryl-1H-pyrazol-3-amine 48 with 3-(dimethylamino)-1-(pyridin-2-yl)prop-2-en-1-one yielded a mixture of regiospecific isomers 50c and 50d. The analogous bicyclic systems 51 were synthesized by reactions of the corresponding aminopyrazoles with enaminonitriles. Also, enaminones 53 and 45 reacted with 5-aryl-1H-pyrazol-3-amine 48 under identical conditions to yield the desired pyrazolopyrimidines 54 and 56 (Scheme 9).⁹¹

3. Reactivity

3.1. Reactivity of substituents linked to ring carbon

3.1.1. Synthesis of aryl ethers

The phenol derivatives 57a–d readily reacted with ditosylates 58 and 61 in acetonitrile containing potassium carbonate to give the respective compounds 59a–c and 62a–d in 64–80% yield. Accordingly, these tosylate derivatives 59a–c and 62a–d reacted with n-Bu₄NF to yield the investigated fluorine-based 60a–c and 63a–d in 81–96% yields (Scheme 10).⁷⁹

Kwon et al.⁹⁴ have detailed the synthesis of acetamides 67a–c in excellent yields through an efficient procedure by reactions of aminopyrazoles 64 with β-diketones 65 in refluxing ethanol. The reductive bond cleavage of the isopropyl ethers 66a–c was achieved by treatment with aluminum chloride in dichloromethane at room temperature, yielding the respective phenols 67a–c. The alkylation of the phenol moiety of compound 67a–c was accomplished by treatment with ditosylates in acetonitrile containing potassium carbonate to yield the alkylated ether products 68 and 70 with tosyl substituents. Subsequent fluorination of 68 and 70 with n-Bu₄NF yielded the particular fluoro-alkyl derivatives 69 and 71 (Scheme 11).

3.1.2. Synthesis of diamides

Palladium-catalyzed Buchwald–Hartwig coupling reactions of iminobenzophenone with aryl bromides 72 under heating conditions in the presence of a ligand, i.e. xanthphos yielded the respective imines 73. Further acidic hydrolysis of the imines 73 with ethanol containing hydrochloric acid yielded the arylamines 74. Next, the amide analogs 76 were synthesized by the reactions of acid chlorides 75 with the amines 74. Base hydrolysis of the ester group of 76 was achieved using lithium hydroxide to give the acids 77. Coupling of the acid derivatives 77 with various amines 78 yielded the diamides 79 using HATU as a coupling agent (Scheme 12).⁹⁵

Predominantly, the reactions of N-alkyliodide salts with methylamine in an alcoholic solution did not give the recyclization products. Therefore, the reaction of 80a with methylamine 81 yielded N-methyl-3-phenyl-1H-pyrazol-5-amine (82) as a major product, besides the formation of aminopyrazole 48 and the dealkylation product 83a. On the other hand, compound 80b reacted with methylamine to afford the dealkylated product 83b as a major product besides aminopyrazole 48, methylaminopyrazole 82, and the acyclic molecule 84. Structure 84 did not cyclize due to the low nucleophilicity of the pyrazole ring that hindered the cyclization step (Scheme 13).⁹⁶

3.1.3. Synthesis of unsaturated ketones

Catalytic reduction of the esters 85 with DIBAL-H in dichloromethane yielded the desired aldehydes 86. Condensation of the aldehydes 86 with acetophenones 87 catalyzed by barium hydroxide in methanol at room temperature gave the anticipated chalcone-based pyrazolopyrimidines 88 (71–91%). Accordingly, the Weinreb–Nahm reactions of aldehydes 86 with N,O-dimethylhydroxylamine hydrochloride catalyzed by trimethylaluminum in dry dichloromethane yielded the respective amides 89. Grignard reaction of 89 with methyl magnesium bromide in dry tetrahydrofuran gave the ketones 90. Further condensation of 90 with various aldehydes 91 in the presence of barium hydroxide in methanol at room temperature produced the respective chalcone-based pyrazolopyrimidines 92 (79–92%%) (Scheme 14).⁹⁷

3.1.4. CH-arylation reactions

Palladium-catalyzed microwave-assisted one-pot reactions of ethyl acetate 93 with aryl halides in toluene accompanied by hydrolysis of the ethyl ester group with lithium hydroxide under microwave irradiation conditions yielded a series of pyrazolopyrimidines 94a–k in 49–80% yields (Scheme 15). The aryl halide, i.e. 1-bromo-3-methylbenzene, is preferred for the synthesis of the target compound 94e (Ar = 2-Me-Ph) with the best yield (64%) over 1-chloro-3-methylbenzene or 1-iodo-3-methylbenzene. The sequence of these reactions involved a direct CH-arylation and subsequent saponification–decarboxylation step-reactions.⁹⁸ The procedure enables the arylation process with high yields, short reaction time, and reduced steps than the outdated methods that involved chlorination of the hydroxy substituents and reaction with (benzyl)zinc(ii) chlorides.^8c,99

3.2. Reactions involving substituents attached to ring nitrogen atoms

The N-alkyliodide salts 96a–c were obtained by reactions of pyrazolopyrimidines 95a and b with alkyl halides such as methyl and ethyl iodides. The bridge nitrogen atom is not favored for alkylation since its lone pair of electrons was included in the aromatization of the ring system. The alkylation was achieved at N4 as indicated by spectral data (Scheme 16).⁹⁶

3.3. Synthesis and reactivity of polycyclic systems

El-Essawy et al.¹⁰⁰ reported the reactivity of hydroxyl substituents at the pyrimidine ring. Therefore, the chlorination of hydroxy derivatives 97 and 100 with phosphorus oxychloride yielded the dichlorinated products 98 and 101, respectively. Nucleophilic substitution reactions of compounds 98 and 101 with sodium azide yielded the bis-azido derivatives 99 and 102. The reactions of chloro-substituted analog 101 with primary amines, i.e. phenyl hydrazine 104, thiourea or aryl or alkyl amines in ethanol or ethanol-containing base yielded the tetracyclic systems 103, 105, and 106 in 78–90% yield. The primary amines in these reactions enable the cyclization process through the substitution of both chlorine atoms (Scheme 17).

Attaby and Eldin¹⁰¹ reported the synthesis of tricyclic pyrazolo–dihydropyrimido–pyrimidinone systems 112 through two-step reactions. Accordingly, the reactions of enaminonitriles 107 and 108 with formic acid yielded the isolated formimidic acids 111 in 60–78% yield through the tautomerization of intermediates 110. The carboxamides 109 also generated intermediates 110 by heating with anhydrous formic acid. The cyclization steps of compounds 111 were accomplished by heating in an acetic acid/acetic anhydride mixture to yield the anticipated products 112 through a cyclocondensation process (Scheme 18).

3.4. Synthesis of binary heterocycles

The reactivity of hydrazide 113 was examined in the reactions with each ethyl ethoxyacrylate 114 and arylidene malononitrile 116 in boiling ethanol to produce the respective cyclocondensation products 115 and 117. The cyclization of the pyrazole ring was accomplished by nucleophilic attack of the amino group of hydrazide at the C3 position of compounds 114 and 116 with the elimination of the ethanol molecule followed by intramolecular nucleophilic attack of the imino group at the nitrile group to give products 115 and 117. Treatment of cyclic aminoester 6 with triethyl orthoformate yielded the (ethoxymethylene)amino-1H-pyrazole 118 in an excellent yield. The reaction of compound 118 with aryl amines in acetonitrile yielded the respective bicyclic pyrazolo[3,4-d]pyrimidinones 119a and b, with the formation of compound 115 as a by-product (Scheme 19).¹⁰²

In a comparable route, condensation of hydrazide 120 with anhydrides in a choline chloride : urea system as a deep eutectic solvent (DES) (it behaves like ionic liquids), which has hydrogen bond acceptors and donors, yielded the 1H-pyrrole-2,5-diones 121a–d in 85–92% yield. The mechanism involved the furan-2,5-dione ring-opening and cyclocondensation steps. Treatment of pyrazolo[1,5-a]pyrimidine 122 with 3-acetyldihydrofuran-2(3H)-one (123) in phosphorus oxychloride yielded the tricyclic 124 as a major product with the formation of the tetracyclic product 125 as a by-product (Scheme 20). The unexpected product 124 was formed through furan ring cleavage utilizing the reactivity of C6 of the pyrimidine ring, cyclization, and chlorination of the hydroxyl groups with phosphorus oxychloride.¹⁰²

4. Biological characteristics

4.1. Antimicrobial activity

Previously, Novinson et al.¹⁰³ have identified the antifungal activities of a series of 7-alkyl-aminopyrazolopyrimidines. Recently, pyrazolopyrimidine 128 was synthesized with a worthy yield (83%) by condensation of 126 with enaminone 127 (Scheme 21). Compound 128 exhibited potent antifungal activity at a concentration of 50 μg mL⁻¹ against G. zeave, A. solani, P. asparagi, and C. arachidicola hori with inhibition potency at 36.4, 45.1, 28.7, 39.6%, respectively. The herbicidal activity of compound 128 evaluated by a cup plate diffusion technique at 100 and 10 μg mL⁻¹ indicated that the compound has a moderate activity at 65.8% and 40.3%, respectively, against B. campestris.¹⁰⁴

Compounds 129a, 129b, 129c, 130, and 131 were tested as antimicrobial agents against Gram-positive bacterial species, e.g. S. aureus and B. subtilis, Gram-negative bacterial species, e.g. P. aeruginosa and E. coli, and fungal strains, i.e. A. niger, A. flavus, and F. moniliforme, using a disc diffusion assay for bacterial species and a dry weight method for fungal tests. Ampicillin and streptomycin were used as antibiotics for bacterial screening tests. The results demonstrated that compounds 129a–c are the most potent antifungal agents compared to compounds 130 and 131 against all fungal strains. Compound 129a had the greatest potency against S. aureus with an inhibition zone at 9–12 mm, while compound 131 had the greatest potency against E. coli with an inhibition zone at 9–12 mm. The pyrazolopyrimidines are more superlative than pyrazolopyrimidin-5(4H)-one skeletons for potent antimicrobial results (Fig. 2).⁸³

The antibacterial potency of pyrazolopyrimidines 115, 117, 119, 121, 124, and 125 was assessed against B. subtilis and E. coli by an agar cup plate procedure. The compounds showed potent antibacterial activities against both bacterial strains compared to streptomycin (16.2 and 16.4 mm). The 1H-pyrazole 115 is more potent against both bacterial species (17.1 and 15.4 mm) than 1H-pyrazole 117 with inhibition zones at 16.1 and 14.2 mm, but compound 117 had a more effective MIC at 20 μg mL⁻¹. In addition, compound 119a (14.3 and 13.1 mm) is more potent than compound 119b (14.0 and 12.2 mm) against B. subtilis and E. coli. The order of the antibacterial potency of molecules of the series 121 was found as compound 121b > 121d > 121a > 121c against B. subtilis, whereas 121b > 121c > 121a > 121d against E. coli. Compound 124 (15.1 mm) is slightly more active than compound 125 (14.1 mm) against B. subtilis, while compound 125 (16.4 mm) is more active than compound 124 (15.3 mm) against E. coli. Compounds 121a and 121d have the highest MIC at 10 μg mL⁻¹; this is comparable to that of streptomycin (5 μg mL⁻¹). On the other hand, compounds 115, 117, 119, 121, 124, and 125 were evaluated as antifungal agents against C. albicans, C. tropicalis, A. niger, and A. clavatus, and griseofulvin was used as a fungal standard. Compounds 117 and 121d have the most potent antifungal agent C. albicans with an inhibition zone of 17.1 and 19.1 mm, higher than the result of griseofulvin (16.8 mm). Moreover, compound 121c had a slightly more potent activity (17.4 mm) than the antibiotic standard against C. tropicalis. Compounds 124 (17.2 mm) and 125 (17.7 mm) are the best active antifungal agents against A. niger and A. clavatus, respectively, with comparable potent activity to that of the antibiotic standard in both cases. In addition, the most effective compounds are 119b and 121d with MIC ranging from 10 to 15 μg mL⁻¹.¹⁰² The SARs was intended as mentioned in Fig. 3.

Hassan et al.⁸⁴ have reported the synthesis of carboxamide analogs 132 by reactions of aminopyrazoles with enaminones, specifically, 3-(dimethylamino)-1-arylprop-2-en-1-ones (Ar₁ = Ph, 4-Me-Ph). In addition, the synthesis of bicyclic pyrazoloquinazoline-carboxamides 133 was accomplished by the reactions of aminopyrazoles with arylidene malononitriles (Ar₂ = Ph, 4-Cl-Ph, 4-F-Ph). Also, the reactivity of aminopyrazoles, viz., 5-amino-3-(phenylamino)-1H-pyrazole-4-carboxamide and 5-amino-3-((4-methoxyphenyl)amino)-1H-pyrazole-4-carboxamide, was extended against the reactions with β-diketones, i.e. ethyl acetoacetate, acetylacetone, and 1,3-diphenylpropane-1,3-dione, through cyclocondensation reactions to yield carboxamide derivatives 134a and b (Ar = Ph, 4-MeO-Ph) and 135a–d (Ar = Ph, 4-MeO-Ph). The different cyclization processes for the construction of both series depended on the type of the β-diketones, in which the asymmetrical β-diketone, i.e. ethyl acetoacetate, gave the series of carboxamides 134a and b, while the symmetrical β-diketones (X = Y = Me or X = Y = Ph) gave the carboxamides 135a–d. The carboxamides 133a, 133d, 135a, and 135c were synthesized according to the method reported by Hafez⁸⁵ (Fig. 4).

Hassan et al.⁸⁴ have also evaluated the antimicrobial characteristics of carboxamides 132, 133, 134, and 135 by a disc diffusion assay against B. subtilis, S. aureus, E. coli, and P. aeruginosa as Gram-positive and Gram-negative bacterial species using tetracycline as an antibiotic. Compounds 132a and 135d are the most potent analogs against all of the microorganisms with more potent activities than the antibiotic standard. The carboxamides of the series 133, 134, and 135 are inactive agents against the tested microbial species except for compound 135d, which showed better activities against all the tested microbial strains. Compounds 132a–d are active antibacterial agents with potent results (MIC: 3.9–7.81 μg mL⁻¹ against B. subtilis, MIC: 7.81–15.62 μg mL⁻¹ against S. aureus, MIC: 15.62–62.5 μg mL⁻¹ against E. coli, and MIC: 7.81–62.5 μg mL⁻¹ against P. aeruginosa). The antifungal activities for carboxamide derivatives 132, 133, 134, and 135 were evaluated against C. albicans, A. niger, A. fumigatus, P. chrysogenum, and F. oxysporum. Amphotericin B was used as a standard antibiotic in this investigation of these series of carboxamides. It was found that compounds 133f and 135b are the most potent antifungal agents against C. albicans (MIC: 15.62 μg mL⁻¹); however, compound 132a is the most potent against A. niger (MIC: 15.62 μg mL⁻¹). In addition, compound 133d showed respectable antifungal activity against A. fumigatus with an inhibition zone at 14.0 ± 0.65 mm (MIC: 15.62 μg mL⁻¹). Compound 135d exhibited the most potent antifungal activities against P. chrysogenum and F. oxysporum (MIC: 15.62 and 7.81 μg mL⁻¹) (Fig. 4).⁸⁴

Kaping et al.⁹² have investigated the synthesis of compounds 136–139 by reactions of the corresponding 3-amino-N-phenyl-1H-pyrazole-4-carboxamide with enaminones under ultrasonic irradiation conditions. In addition, Kaping et al.⁹³ have also investigated the synthesis of analogous pyrazolopyrimidine-based carboxamidoantipyrine substituents by reactions of aminopyrazoles with enaminones under ultrasonic irradiation conditions. The antibacterial activity of 3-(carboxamido)-pyrazolopyrimidines 136–139 was evaluated by Kaping et al.⁹² against diverse bacterial species, i.e. B. subtilis, E. coli, S. enterica, and S. aureus. The results of the disc diffusion assay demonstrated that the compounds exhibited no activity against B. subtilis, and compounds 136a (10 mm), 136d (17 mm) and 139b (19 mm) inhibited the growth of S. aureus with high potency relative to the result of ampicillin (21 mm). The compounds showed better antibacterial activities against both Gram-negative bacterial species. Compounds 136a (10 mm), 136c (10 mm), 136d (10 mm), 136e (11 mm), 138a (12 mm), and 139c (10 mm) revealed potent activities against E. coli compared to the antibiotic standard (11 mm). Also, compounds 138a (23 mm), 138c (11 mm), 138d (20 mm), and 139a (16 mm) showed potent antibacterial activities against S. enterica bacterial species relative to the result of ampicillin (23 mm). The SARs of the compounds as antibacterial agents are shown in Fig. 5.

Two series of pyrazolopyrimidines were prepared by reactions of aminopyrazoles with unsaturated ketones under reflux conditions as stated by Abdallah et al.¹⁰⁵ The compounds of both series were assessed as antimicrobial agents against Gram-positive bacteria, i.e. B. subtilis, S. aureus, Gram-negative bacteria, i.e. E. coli and P. aeruginosa, and fungal species, i.e. A. flavus and C. albicans, using a disc diffusion assay. The results revealed that compound 142b has potent antibacterial activity against B. subtilis (12 mm) and E. coli (11 mm) relative to the results of the antibiotic ampicillin (26 and 25 mm). Definitely, compounds 142a, 142b, 142d, 142h, 144a, 144e, 144f, 144h, 144i, 144l, and 144n revealed a good antibacterial spectrum against B. subtilis (9–14 mm). Compounds 144c, 144g, 144i, and 144n showed good activity against S. aureus (9–14 mm), while compounds 142b, 144e, 144i, and 144n revealed potent activities against E. coli species (9–12 mm). Consistently, compounds 142a, 142b, 142d, 142h, 144a, 144e, 144f, 144i, 144j, 144l, and 144n presented potent antibacterial activities against P. aeruginosa species (9–12 mm). The other tests presented negative results, including the antifungal potency, as the compounds have no activity to inhibit or kill some bacterial or fungal species (Fig. 6).

Otherwise, pyrazolopyrimidines were obtained by reactions of the desired aminopyrazoles with enaminones or from a multicomponent step or one-pot reactions of diaminopyrazoles with triethyl orthoformate and diarylsulfonyl acetaldehydes by heating acetic acid under thermal or microwave conditions.¹⁰⁶ The antimicrobial activities of compounds 145a–d, 145h, 146a, and 146c–h (Fig. 7) were assessed by a disc diffusion method against fungal species (A. niger and G. candidum), Gram-positive bacterial species (S. aureus, S. epidermidis, B. subtilis, and S. pyogenes), and Gram-negative bacterial species (P. aeruginosa, E. coli, K. pneumoniae, and S. typhimurium). The results declared that compounds 146c (inhibition zone diameter = 25.1 ± 1.2 mm) and 146g (26.3 ± 0.63 mm) presented more potent antifungal activities than amphotericin B (23.3 ± 0.58 mm) against A. niger, while compound 146d (25.2 ± 1.2 mm) has the same result as the antibiotic against G. candidum. Alternatively, the most effective potency was recorded for compounds 146c (23.4 ± 0.63 mm) against S. aureus, 146d (22.6 ± 0.72 mm) against S. epidermidis, 146f (26.5 ± 0.58 mm) against B. subtilis, and inactive potency against S. pyogenes. For Gram-negative species, compounds 146d (25.7 ± 1.2 mm) and 146g (25.5 ± 1.2 mm) have more potent activities against E. coli compared to gentamicin (25.4 ± 1.2 mm), compound 146d (26.6 ± 1.2 mm) against K. pneumoniae, and compounds 146c (26.3 ± 0.58 mm), 146d (26.2 ± 0.58 mm), and 146g (26.6 ± 0.72 mm) against S. typhimurium, whereas these molecules are inactive against P. aeruginosa. Compounds 146c, 146d, and 146g revealed the minimum inhibitory concentrations of 0.49–31.25 μg mL⁻¹ in ranges matched with those of the antibiotic standards.

In addition, pyrazolopyrimidines were synthesized recently by Fouda et al.¹⁰⁷ in remarkable yields, and after a short reaction time via reactions of the corresponding diaminopyrazole with unsaturated nitriles in ethanol/pyridine mixture under thermal or microwave-assisted or sonication conditions. These compounds (Fig. 8) were appraised as antimicrobial agents against S. aureus, B. subtilis, and S. mutans (Gram-positive bacteria), E. faecalis, P. vulgaris, and E. coli (Gram-negative bacteria), and A. fumigates, A. flavus, and C. albicans using the disc diffusion assay at concentrations of 5 mg mL⁻¹. Gentamycin and ketoconazole were applied as standard antibiotics for bacterial and fungal species, respectively. Compound 150b revealed remarkable activities against E. faecalis (25 mm) and P. vulgaris (40 mm) along with good activities against all other microbial species with inhibition zones ranging from 13 to 25 mm. In addition, compound 150a presented insignificant antibacterial activities against the tested bacterial species (inhibition zones = 9–18 mm) along with no antifungal activities. Compounds 147a, 147b, 148a, 148b, 149a, 149b, 151a, 151b, and 152 revealed no antimicrobial activities in all cases except for compounds 147a, 147b, and 148b that revealed moderate activities against E. coli (10 mm), B. subtilis (8 mm), and S. aureus (10 mm), respectively.

Sheikhi-Mohammareh et al.¹⁰⁸ have developed the synthesis of tetracyclic systems 155a–i by gently heating carbonitrile 153 with 2-amino-N-substituted-benzamides 154 in DMF catalyzed by potassium carbonate (Scheme 22). The tetracyclic systems were evaluated as antibacterial agents against K. pneumoniae and E. coli at seven concentrations of serial dilutions of each sample (15.6–1000 ppm). The lower concentrations of the samples revealed good efficiency to decrease the growth of the strains relative to clinical ones. Compound 155h was found as the lone compound that can impede the growth of multi-drug-resistant hospital bacteria isolated from UTI victims with 100% growth inhibitory activity on both categories of bacterial species.

A series of pyrazolopyrimidines 156a–j (Fig. 9) were efficiently synthesized by reactions of the corresponding aminopyrazoles with arylidene malononitriles in ethanol containing a catalytic amount of trimethylamine under heating conditions.¹⁰⁹ Accordingly, these compounds were evaluated by in vitro assay as antimicrobial agents against a diversity of microbial species. Thus, compounds 156b, 156e (IZ = 20 mm), and 156j (IZ = 21 mm) are the most potent agents against B. subtilis species: however, the same compounds are the most active agents with inhibition zone diameters of 16 mm against E. coli species. On the other hand, compounds 156d, 156e, 156f, 156g, and 156i introduced improved antifungal activities against A. niger species with inhibition zone diameters ranging from 15 to 18 mm. Also, most of the compounds are potent antifungal agents against C. albicans species; in particular, compound 156f is the most effective agent (IZ = 18 mm) compared to cycloheximide (32 mm). Lately, Metwally et al.¹¹⁰ have in vitro estimated the antibacterial potency of the proficiently synthesized pyrazolopyrimidines under bio-catalytic conditions using pepsin by applying a green protocol.

4.2. Antimalarial activity

Azeredo et al.¹¹¹ have investigated the preparation of pyrazolopyrimidines 159a–o (Scheme 23) by reactions of aminopyrazoles with 1,3-diketones, followed by chlorination with POCl₃ and nucleophilic substitution of the chlorine atom with aryl amines in multi-step reactions. The compounds 159a–o were assessed against P. falciparum (W2 clone, chloroquine-resistant) for cytotoxicity in BGM cells and percent inhibition of the PfDHODH enzyme. The results revealed that thirteen compounds have in vitro anti-P. falciparum activity against chloroquine-resistant parasites (IC₅₀ = 1.2–92.4 μM). Compounds with 2-naphthyl substituents (Ar = 2-naphthyl) (159d: R₁ = CF₃, R₂ = CH₃, 159j: R₁ = R₂ = CH₃, 159o: R₁ = CH₃, R₂ = CF₃) and 3,5-dimethoxyphenyl (159m: R₁ = CH₃, R₂ = CF₃) at the 7-position exhibited the most potent activities. The in vitro and inhibitory percentage of PfDHODH indicated that compounds 159a (Ar = 4-Cl-Ph, R₁ = CF₃, R₂ = CH₃), 159b (Ar = 3,5-(MeO)₂-Ph, R₁ = CF₃, R₂ = CH₃), 159d (Ar = 2-naphthyl, R₁ = CF₃, R₂ = CH₃), 159e (Ar = 4-CF₃-Ph, R₁ = CF₃, R₂ = CH₃), 159h (Ar = 3,5-(MeO)₂-Ph, R₁ = R₂ = CH₃), 159j (Ar = 2-naphthyl, R₁ = R₂ = CH₃), 159k (Ar = 4-CF₃-Ph, R₁ = R₂ = CH₃) and 159o (Ar = 2-naphthyl, R₁ = CH₃, R₂ = CF₃) have the maximum percentage inhibitions. Other recent research reported the use of 8-aminoquinoline-pyrazolopyrimidines and 7-arylaminopyrazolopyrimidines as antimalarial agents.¹¹² Similar recent reports are related to the evaluation of the biological potency of pyrazolopyrimidines or their isomeric structures as anti-P. falciparum agents.^113,114

4.3. Antiproliferative activity

The cytotoxicity of chalcone-based pyrazolopyrimidines 88 and 92 was appraised using an MTT assay against A549, MDA-MB-231, DU-145, and HEK293 cells.⁹⁷ The results showed potent activities relative to the reference standard, erlotinib, with inhibitive potentials ranging from IC₅₀ = 2.6 μM to 34.9 μM. In brief, compounds of analogs 88 revealed more potent cytotoxicity than the compounds of analogs 92. Both series have the same structure except for the orientation of the enone bond, in which the carbonyl group adjacent to the pyrazolopyrimidine ring system reduces the potency of the compounds as cytotoxic agents. The most potent analogs are compounds 88b (R₁ = 4-OMe, R = 4-OMe), 88h (R₁ = 3,4-diOMe, R = 3,4-diOMe), and 88i (R₁ = 3,4-diOMe, R = 3,4,5-triOMe) with high efficiency in inhibiting the growth of cancer cells along with low cytotoxicity against human embryonic kidney (HEK293) cells. The SARs of both series in Fig. 10 presented the effect of the position of the enone motif linked to the pyrazolopyrimidine scaffold and the nature of substituents on the phenyl ring on the potency of the molecules as cytotoxic agents.⁹⁷

4.4. Cytotoxic activity

Kamal et al.¹¹⁵ have deliberated the synthesis of benzoylpiperazinyl methanones 160a–x by condensation of 2-phenyl-7-(substituted-aryl)pyrazolo[1,5-a]pyrimidine-5-carboxylic acids with piperazin-1-yl(2-((aryl-methyl)amino)phenyl)methanones in dichloromethane under catalytic conditions of EDCI/HOBt by stirring at 0 °C to room temperature. The respective pyrazolo[1,5-a]pyrimidinyl amides 160a–x were assessed in vitro as anticancer agents using the MTT assay on human cervical cancer, i.e. HeLa and SiHa cell lines, in which roscovitine was used as a standard anticancer drug. The results verified that compound 160r is the most active agent on SiHa cells with IC₅₀ = 1.56 ± 0.30 μM; thereafter, compound 160l has the second strongest influence with IC₅₀ = 1.61 ± 0.30 μM, 160q has the second strongest potency with IC₅₀ = 1.81 ± 0.22 μM, and compounds 160f, 160g, and 160t with IC₅₀ = 1.91 ± 0.17, 1.93 ± 0.32, and 1.99 ± 0.17 μM, respectively. All these compounds have higher potency than the anticancer standard, roscovitine (IC₅₀ = 2.69 ± 0.35 μM). The rest of the compounds demonstrated good cytotoxicity (IC₅₀ = 2.04 ± 0.48 to 2.71 ± 0.12 μM) relative to the standard anticancer on SiHa cell lines. On the other hand, compounds 160c (IC₅₀ = 1.81 ± 2.24 μM), 160d (IC₅₀ = 1.89 ± 0.13 μM), 160f (IC₅₀ = 1.51 ± 0.20 μM), 160j (IC₅₀ = 1.73 ± 0.18 μM), 160k (IC₅₀ = 1.56 ± 0.12 μM), 160l (IC₅₀ = 1.54 ± 0.18 μM), 160q (IC₅₀ = 1.99 ± 0.17 μM), 160r (IC₅₀ = 1.46 ± 0.15 μM), 160s (IC₅₀ = 1.95 ± 0.19 μM), 160t (IC₅₀ = 1.99 ± 0.64 μM), 160v (IC₅₀ = 1.95 ± 0.42 μM), and 160x (IC₅₀ = 1.76 ± 0.24 μM) exhibited the most potent cytotoxicity on the HeLa cell line, higher than that of roscovitine (IC₅₀ = 2.20 ± 0.12 μM). The SARs of the tested compounds as shown in Fig. 11 demonstrated that the substitution of the phenyl ring (R₁–R₃) has a great impact on the anticancer potency of the compounds, but the most effective core is related to the pyrazolo[1,5-a]pyrimidine skeleton based on the reasonable influences of most of the compounds relative to the anticancer standard.

Kamal et al.^7b have prepared carboxamide analogs 161a–t (Fig. 12) by condensation of 2-phenyl-7-(substituted-aryl)pyrazolo[1,5-a]pyrimidine-5-carboxylic acids with 5,6-disubstituted-benzo[d]thiazol-2-amines in dichloromethane under the same preceding conditions (EDCI/HOBt, CH₂Cl₂, 0 °C → rt, 8 h). The anticancer activity of carboxamides 161a–t was evaluated in vitro by the MTT assay on various tumor cells, i.e. lung (A549), prostate (DU-145), breast (MCF-7), renal cell carcinoma (ACHN), cervical (HeLa), using roscovitine as an anticancer standard. The results verified that compounds 161m, 161n, and 161p exhibited the most potent cytotoxicity with IC₅₀ = 1.94, 1.54, and 2.01 μM, respectively, while compounds 161l, 161s, and 174t are strong cytotoxic agents with slightly lower efficiency on lung cell lines (A549) relative to the anticancer standard (IC₅₀ = 2.18 μM). The most potent cytotoxic agents were found to be 174m, 174n, and 174p with IC₅₀ = 2.08, 2.95, and 3.16 μM, respectively, on the prostate cell line DU-145; the less potency of the same compounds on this cancer cell line is due to the nature of the tumor cell that affects the obtained results. Compounds 161l, 161m, 161n, 161p, 161s, and 161t revealed more potent anticancer activities with IC₅₀ = 2.95, 2.29, 2.23, 2.88, 2.51, and 2.29 μM, respectively, than the anticancer standard (IC₅₀ = 3.98 μM) on the breast cancer cell line MCF-7. The most potent cytotoxic agent for renal cell carcinoma (ACHN) was compound 161n (IC₅₀ = 1.69 μM), while compound 161m (IC₅₀ = 2.63 μM) was the strongest cytotoxic agent for cervical (HeLa) cell lines. On the other hand, compounds 161a–k exhibited good to moderate cytotoxic activities on all the tumor cell lines. Fig. 12 presented the SARs of the tested compounds as potent antitumor agents.^7b

Kamal et al.⁷⁶ reported the synthesis of diamides 163a–x (Scheme 24) by coupling carboxylic acids 15 with tert-butyl carboxylates 162 through two step-synthesis. The first step involved the acid cleavage with the removal of the Boc-protection on the piperazine core of compounds 162 followed by the coupling process in the second step. The compounds were evaluated as anticancer agents against SiHa, MCF-7, HeLa, and IMR-32 tumor cell lines by the MTT assay. The results indicated that compounds 163a (R₁ = R₃ = H, R₂ = F, R₄ = Ph) and 163c (R₁ = R₃ = H, R₂ = MeO, R₄ = Ph) were the most effective among this series against the tested cell lines. Generally, compounds 163a, 163c, 163j (R₁ = R₂ = R₃ = MeO, R₄ = 4-F-Ph), 163m (R₁ = R₃ = H, R₂ = MeO, R₄ = 4-MeO-Ph), 163o (R₁ = R₂ = R₃ = MeO, R₄ = 4-MeO-Ph), 163q (R₁ = H, R₂ = R₃ = Cl, R₄ = 3,4-(MeO)₂-Ph), 163r (R₁ = R₃ = H, R₂ = MeO, R₄ = 3,4-(MeO)₂-Ph), 163s (R₁ = H, R₂ = R₃ = OMe, R₄ = 3,4-(MeO)₂-Ph), 163t (R₁ = R₂ = R₃ = MeO, R₄ = 3,4-(MeO)₂-Ph) and 163w (R₁ = R₃ = H, R₂ = MeO, R₄ = 3,4,5-(MeO)₃-Ph) revealed potent cytotoxicity to all tumor cells relative to the results of the reference standard, doxorubicin. Compound 163a presented the highest effective cytotoxic influence on the verified tumor cell lines with IC₅₀ = 2.65, 1.79, 2.29, and 4.65 μM, respectively. Compound 6c exhibited a second-order cytotoxic capacity with IC₅₀ = 3.33, 2.16, 2.43, and 4.75 μM, respectively, against all the tested tumor cell lines (Scheme 24).

Compounds 164 were tested as anticancer agents using the MTT assay against HeLa with cisplatin as a reference standard. Compounds 164q, 164u, and 164w exhibited potent cytotoxicity with IC₅₀ less than 10 μM and were considered more potent than cisplatin (IC₅₀ = 17.83 μM) used as an anticancer drug. The SARs of the tested diamides 164 are presented in Fig. 13.⁹⁵

Bagul et al.⁹⁷ have reported the synthesis of two series of the relevant pyrazolopyrimidinyl chalcones; one of them (series 88a–q) was prepared by the reactions of β-ketoesters with 3-amino-5-phenyl-pyrazole in boiling ethanol in acid medium, followed by reductive cleavage of the formed esters to the aldehydes, which condensed with active methylenes to yield series 88a–q. The other series 92a–k was prepared through the transformation of the previously prepared aldehydes in the last series to the respective acetyl analogs, which reacted with aryl aldehydes by condensation catalyzed by barium hydroxide in methanol at room temperature. The molecules of the two series were assessed as anticancer agents against A549, MDA-MB-231, and DU-145 tumor cells using an MTT assay (Fig. 14).

Compounds 88a–c (8.6, 2.9, 7.4 μM), 88f (9.3 μM), 88h (3.9 μM), and 88i (7.2 μM) revealed the strongest cytotoxicity on A549 cell line than erlotinib (10.39 μM). In addition, compounds 88a–d (9.9, 6.3, 8.7, 11.8 μM), 88f (9.3 μM), 88f–i (11.5, 13.9, 2.6, 4.7 μM), 88m (13.5 μM), 88n (13.2 μM) and 92i (14.19 μM) revealed the most potent cytotoxicity to the MDA-MB-231 cell line than the standard erlotinib (14.74 μM). Compounds 88a–d (13.7, 8.5, 16.4, 10 μM), 88f (9.3 μM), 88f–i (12.1, 14.6, 7.2, 8.3 μM), 88m (15.4 μM), 92a–d (15.57, 19.49, 14.93, 14.74 μM), 92f (16.31 μM), 92h (16.91), 92i (15.33), and 92j (17.91 μM) revealed the most potent cytotoxicity to the DU-145 cell line in comparison to erlotinib (18.4 μM). The substitution of the phenyl ring with one or two methoxy groups (R₁ = OMe or diOMe) is preferred for potent anticancer potency. Generally, the substituents at the phenyl ring attached to the chalcone moiety (R = 4-OMe, 3,4-diOMe and 3,4,5-triOMe) are perfect for potent cytotoxicity than the unsubstituted or substituted electronegative substituents at the phenyl rings. Series 88 are more potent cytotoxic agents than series 92, indicating the role of the chalcone moiety and the effect of linkage position (Fig. 14).⁹⁷

The compounds 167 and 168 (Fig. 15) were tested as anticancer agents on the MCF-7, HepG2, HCT116, and PC3 cell lines by the SRB assay using tamoxifen as a scale standard. The molecules, in general, showed no activities against the HCT116 and PC3 cell lines. In addition, compound 167 is more potent with IC₅₀ = 21.9 ± 2.3 μg mL⁻¹ than compound 168 that has IC₅₀ = 39.7 ± 4.7 μg mL⁻¹. Compounds 167 and 168 in general are less potent than tamoxifen (IC₅₀ = 8.50 ± 0.90 μg mL⁻¹). The influence of the chlorine atom decreased the potency of 168 against the MCF-7 cell lines.¹¹⁶

A series of bicyclic and tricyclic carboxamides 42 and 46 were evaluated as anticancer agents against HepG-2 and MCF-7 tumor cells by employing the MTT assay. The carboxamide 42h is the greatest cytotoxic agent to the HepG-2 cell line (IC₅₀ = 70.3 ± 4.1 μg mL⁻¹) compared to doxorubicin (IC₅₀ = 80.9 ± 2.1 μg mL⁻¹). In general, all the compounds of these series presented strong cytotoxicity to both cancer cells. Compounds 42c and 46a recorded the second order of potency on the HepG-2 cell line (IC₅₀ = 76.2 ± 3.9 and 77.6 ± 4.3 μg mL⁻¹). Alternatively, compounds 42a–c offered the greatest cytotoxicity to the MCF-7 cell line (IC₅₀ = 63.4 ± 3.6, 63.2 ± 5.9, and 64.0 ± 2.8 μg mL⁻¹) compared to the reference standard (IC₅₀ = 65.6 ± 4.2 μg mL⁻¹). The other compounds showed potent cytotoxicity equal to or near that of the reference standard (Fig. 16).⁸⁷

El-Naggar et al.⁸⁶ have prepared two series of pyrazolopyrimidines via reactions of the aminopyrazoles with either acyclic enaminones or cyclic enaminones in acetic acid. The anticancer activity was assessed in vitro on HepG-2 and MCF-7 tumor cell lines employing the MTT assay, in which doxorubicin was used as a specific anticancer agent. The results revealed that compounds 42c, 42d, 42h, 42j, 42k, 42l, 42o, 42q, 42r, 42s, 42t, and 46c (Fig. 17) (IC₅₀ = 72.2–79.5 μM) exhibited marginally higher cytotoxic activities than doxorubicin (IC₅₀ = 80.9 ± 2.1 μM) on HepG-2 cancer cells. Additionally, compounds 42a, 42b, 42c, 42j, and 42u presented slightly higher cytotoxic effects than doxorubicin (IC₅₀ = 65.6 ± 4.2 μM) on MCF-7 cell lines. The most efficient compound is 42o (IC₅₀ = 72.2 ± 3.8 μM) against HepG-2 cancer cells, while the most effective one on MCF-7 tumor cell lines was found to be compound 42a (IC₅₀ = 63.1 ± 3.1 μM).

The development and the progress of prostate cancer (PCa) were focused on in the past decades on applying the androgen receptor (AR), which has a serious role in contemporary androgen deprivation therapy. Nonsteroidal antiandrogens were effectively used for the treatment of prostate cancer, but with drug resistance after a year and a half. Wang et al.¹¹⁷ have identified a combination of structure- and ligand-based methodologies to obtain potent androgen receptor antagonists. In this sequence, the rate of inhibition of PCa- and DHT-induced transcriptional activation of androgen receptors was evaluated in vitro for a series of pyrazolopyrimidines 169–172 (Fig. 18) to identify their potential antagonistic effects. Compound 171 showed potent results (IC₅₀ = 23.4 ± 4.0 μM) compared to that of R-bicalutamide (IC₅₀ = 24.6 ± 4.5 μM), while compound 172 exhibited a potential antagonistic effect with IC₅₀ = 45.8 ± 2.3 μM in the second order of potency by applying a cell proliferation assay. The representative mechanism estimated that compound 171 prevented H12 in AR LBD from closing to distort the formation of AF2 with invalid transcription. The series of this class of heterocycles with an antiandrogenic scaffold functions as a core structure of an androgen receptor antagonist. It is worth mentioning that the substituents at the C2 position of bicyclic pyrazolopyrimidines are preferred to be aryl substituents with the carboxylic group at the p-position, while the substituents at the C2 position are better to be aryl substituents substituted with electron-donating groups for potent cytotoxicity.

The cytotoxic potency of pyrazolopyrimidines 147–151a and b and 152 (Fig. 8) was evaluated in vitro by the MTT assay against tumor cells such as HepG-2, HCT-116, and MCF-7 cell lines. The results verified that compounds 147b (0.3 ± 0.01 μg mL⁻¹), 150b (4.5 ± 0.4 μg mL⁻¹), and 151b (1.4 ± 0.03 μg mL⁻¹) have potent cytotoxicity to MCF-7 cells relative to doxorubicin (1.2 ± 0.2 μg mL⁻¹). In the case of the HepG-2 cell line, compounds 147b (0.6 ± 0.2 μg mL⁻¹), 150b (3.9 ± 0.4 μg mL⁻¹), 151b (3.4 ± 0.6 μg mL⁻¹), and 152 (4.1 ± 0.3 μg mL⁻¹) have the most potent cytotoxicity (doxorubicin, IC₅₀ = 0.9 ± 0.3 μg mL⁻¹). On the other hand, compounds 147b (0.4 ± 0.02 μg mL⁻¹), 150b (2.7 ± 0.6 μg mL⁻¹), and 151b (2.4 ± 0.4 μg mL⁻¹) exhibited the most potent cytotoxicity to the HCT-116 cell line relative to doxorubicin (1.6 ± 0.2 μg mL⁻¹). Generally, compound 147b is the most effective cytotoxic agent compared to the other compounds on the different tumor cells.¹⁰⁷

Fayed et al.⁸⁰ reported the cytotoxic activity of a series of substituted pyrazolopyrimidines 27–30, 34, 37, and 39 against HepG-2, HCT-116, and MCF-7 cell lines by the MTT assay. The results showed that the series of compounds 37 and 39 are the most potent cytotoxic agents against the HepG-2 cell line with IC₅₀ = 0.64–24.8 μg mL⁻¹. The most potent analog is compound 37b with IC₅₀ = 0.64 μg mL⁻¹. Additionally, compounds 37b and 39a presented the highest efficiency in inhibiting the growth of the HCT-116 cancer cell lines with IC₅₀ = 1.89 and 2.39 μg mL⁻¹, with more potent activity than the reference standard (2.9 μg mL⁻¹). Consistent results are recorded for the same compounds against the MCF-7 cell lines with IC₅₀ = 2.79 and 3.09 μg mL⁻¹, with effectiveness higher than that of Taxol (4.7 μg mL⁻¹). The SARs was discussed as verified in Fig. 19.

Kaping et al.⁹¹ have synthesized arylpyrazolopyrimidines 49–51, 54, and 56 through reactions of aminopyrazole with either enaminones or enaminonitriles in a water/ethanol mixture under KHSO₄ catalytic conditions. Compounds 50c and 50d were obtained as products from the reaction of aminopyrazole with 3-(dimethylamino)-1-(pyridin-2-yl)prop-2-en-1-one in 41% and 45% yield. The anticancer activities were evaluated for compounds 49–51, 54, and 56 thru the MTT assay on CHO K1 cell lines. Compound 50c exhibited the most reduction in the color of MTT after exposure to the cancer cells relative to the unexposed cell lines. The order of decreased absorbance was found as follows, 54b, 50a, 56, 49a, 50d, 54c, 51c, 51b, 49c, 50b, and 51a, in which these compounds are believed to present remarkable cytotoxic potency on CHO K1 cell lines. The compounds of these series could be applied significantly on a large scale as cytotoxic agents against CHO K1 tumor cell lines. The SARs indicated that (1) the 2-aryl-pyrazolopyrimidine moiety is the most effective core that controls the cytotoxic effect. (2) The incorporation of pyridinyl substituents (compounds 50a–d) provided the most potent cytotoxicity, in which 2-pyridyl is more effective than the other isomeric structures. (3) The electron-donating group (amino group of compounds 51a–c) led to improved cytotoxicity. (4) The methyl ester substituent (compounds 54a–c) is essential for potent cytotoxic effect compared to the ethyl ester analog or the acetyl one. (5) The tricyclic system (compound 56) provided potent cytotoxicity (Fig. 20).

Kaping et al.⁹³ have synthesized compounds 173–177 starting from 3-amino-N-antipyrinyl-1H-pyrazole-4-carboxamide following their preceding synthetic procedure under the same conditions (in H₂O/EtOH, KHSO₄ acid medium under ultrasonic irradiation, at 60 °C).⁸⁷ The cytotoxic effects of the series of pyrazolopyrimidines 173–177 were assessed by MTT colorimetric assay on CHO K1 cells. It was found that compounds 173a, 173b, 174a, 174b, 177a, and 177b reduced the metabolism of MTT solution caused by the action of the enzymes of CHO K1 cells. The order of decreased metabolism of MTT solution was recorded for compounds 173a (97.10%), 174b (72.96%), 177a (72.46%), 177b (49.24%), 174a (45.75%), and 173b. Therefore, compounds 173a, 173b, 174a, 174b, 177a, and 177b have cytotoxic properties on CHO K1 cell lines (Fig. 21).

Four series of pyrazolopyrimidine compounds 179–182a–d (Fig. 22) were synthesized recently by Elgiushy et al.¹¹⁸ utilizing the reactivity of β-aminoketones 178a–d towards one-pot reactions with each of acetyl acetone, ethyl acetoacetate, 1,3-diphenylpropane-1,3-dione, and ethyl 3-oxo-3-phenyl propanoate, respectively, under acidic conditions. The results of the antitumor activity indicated that compound 181a exhibited the most potent activity with 48.5% inhibition against the growth of the 60-NCI cancer cell line relative to the other tested compounds (0.5–10.72%). In addition, the results of in vitro MTT assay confirmed that compound 181a presented very strong potential activity against the HCT-116 colorectal cancer cell line (IC₅₀ = 6.28 ± 0.26 μM) and strong activity against normal WI-38 cell line (IC₅₀ = 17.7 ± 0.92 μM). The cell cycle over apoptosis detection flow-cytometry and the analysis of gene expression revealed a pro-apoptotic effect of compound 181a with increased expression of p53, Bax, cytochrome c, and caspases along with decreased expression of Bcl-2, thus, the exertion of a pro-apoptotic effect through an intrinsic path. Also, compound 181a showed good potency for CDK1 inhibition (IC₅₀ = 161.2 ± 2.7 nM) relative to roscovitine (IC₅₀ = 81.7 ± 1.5 nM).

Sabita et al.¹¹⁹ have reported a multistep synthesis for the construction of isoxazolyl-pyrazolopyrimidines 183a–j (Fig. 23) and assessed their cytotoxic activity against a diverse tumor cell line by applying the MTT assay. The results indicated potent activities for compounds 183a (IC₅₀ = 0.18 ± 0.069 μm), 183b (IC₅₀ = 0.99 ± 0.052 μm), 183c (IC₅₀ = 1.77 ± 0.96 μm), 183d (IC₅₀ = 2.1 ± 1.25 μm) and 183e (IC₅₀ = 0.08 ± 0.005 μm) against the SiHa cell line. The most potent cytotoxicity was recorded by compounds 183a (IC₅₀ = 0.01 ± 0.0043 μm) and 183e (IC₅₀ = 0.054 ± 0.006 μm) against the A549 cell line. The most potent cytotoxicity was also recorded for compound 183a (IC₅₀ = 0.01 ± 0.0043 and 0.1 ± 0.047 μm) against MCF-7 and Colo-205 cells, respectively. Generally, compounds 183a–e are the most potent cytotoxic agents against all the assessed cell lines.

A new series of diaryl-pyrazolopyrimidines 184a–i (Fig. 24) were efficiently synthesized by Ballesteros-Casallas et al.¹²⁰ and assessed in vitro as cytotoxic agents against HCT-116 and HEK 293 cell lines. Compounds 184d (percentage of cell viability = 26.0 ± 2.3%) and 184h (percentage of cell viability = 37.0 ± 2.3%) revealed the most potent activities against HCT-116 tumor cells. Otherwise, exceptional compounds 184i (percentage of cell viability = 44.2 ± 0.4%) and 184b (percentage of cell viability = 48.0 ± 0.1%) demonstrated good cytotoxic effects compared to the other tested compounds with the most decreased percentages of cell viabilities against HEK 293 cell lines. More recently, Bhogireddy et al.¹²¹ have established the anticancer potency of arylpyridinyl-isoxazolyl-pyrazolopyrimidines on PC3 (prostate), DU-145 (prostate), A549 (lung), and MCF-7 (breast) tumor cell lines.

4.5. Anti-inflammatory activity

The anti-inflammatory properties of compounds 49–51, 54, and 56 were evaluated using tissue swelling (edema) and nitric oxide assays. The potent anti-inflammatory potency of the tested compound measured the efficiency of the compound to decrease vascular penetrability in the reduction process of the edema. The paw diameter was measured at different intervals of time, ensued a decrease in the paw diameter of some molecules. The results indicated that compounds 49a, 49b, 49d, 49e, 50b, 51c, 54a, and 54b revealed good inhibition for paw edema. In addition, bicyclic compounds 6a, 6d, and 8b presented the same potency of paw edema inhibition at 24 h relative to the control group. On the other hand, the nitric oxide assay was used for the evaluation of the anti-inflammatory activity of these compounds as the potent analog can reduce the production of nitric oxide. Compounds 54a, 54b, 50c, 50d, 50a, 49e, 50b, 51a, and 51c revealed reduced concentration in nitric oxide when paw exudates of mice inflamed with FCA were treated with the investigated compound. The nitric oxide concentrations in blood were measured with varying levels, indicating that compound 54c has the highest level of reduction of nitric oxide concentration, followed by 50c, 51b, 56, and 54a. In addition, compounds 49d, 49e, 50b, 50d, and 51a showed a high level of concentration reduction in NO with equivalent grades; nevertheless, compounds 49a and 49c (Fig. 20) are inactive with no reduction in NO concentration.⁹¹

Kaping et al.⁹¹ have also reported the evaluation of pyrazolopyrimidines as anti-inflammatory agents by paw diameter as percentage inhibition and nitric oxide assay. The results of the paw diameter assay indicated that 2-aryl-pyrazolopyrimidines 49a, 49b, 49d, 49e, 50b, 51c, 54a, and 54b presented inhibition of paw edema. In addition, compounds 50a, 50d, and 51b revealed an equivalent inhibition of paw diameter after 24 h relative to the controlled untreated group. On the other hand, the nitric oxide assay demonstrated that the mice inflamed with FCA revealed a reduction in nitric oxide concentration using compounds 54a, 54b, 50c, 50d, 50a, 49e, 50b, 51a, and 51c (Fig. 20).

The anti-inflammatory activity was evaluated for this series of pyrazolopyrimidines 173–177 (Fig. 21) through paw edema and nitric oxide assays using ibuprofen as a standard. The highest percentage of inhibitions of the edema in the paw diameter of the mice at 24 h were recorded for compounds 174b (25%) and 177a (16.57%). However, at 4 h the highest effects were recorded for compounds 174b, followed by compounds 175, 177a, 177b, 173a, 173c, 173e, and 176, while the standard ibuprofen revealed the highest percentage of inhibition of up to 66.67% at 4 h. On the other hand, compound 177b exerted a remarkable reduction in NO concentration in paw exudates, even though compound 173a revealed an approximate reduction magnitude in blood. Compounds 174b and 177b are associated with the maximum aptitude to decrease the noticeable indicators of inflammation, neutrophils and eosinophils.⁹³

Abdelgawad et al.¹²² have reported the synthesis of a series of pyrazolopyrimidines 186a–e through a simple procedure that involved the utility of the reactive pyrazole precursor 185 in reactions with a variety of unsaturated nitriles or β-diketones. The anti-inflammatory activity was estimated for these series of compounds through in vivo and in vitro techniques. Alternatively, compound 186b (Fig. 25) was appraised as the most effective agent against IL-6 (80%) and TNF-α (89%). A potent inhibitory impact was recorded for compound 186c against COX-2 (IC₅₀ = 1.11 μM) along with extreme selectivity against COX-2 (S.I = 8.97) recorded for compound 186b. The edema assay investigated respectable potency for compounds 186b–e (46–68%) with the most effective influence for compound 186b (ED₅₀ = 35 mg kg⁻¹). Also, compounds 186b (IC₅₀ = 1 μM) and 186d (IC₅₀ = 1.7 μM) revealed the most effective inhibitions for sPLA2-V. The potency of the compounds against 15-LOX presented a good potential inhibition for compound 186c (IC₅₀ = 5.6 μM) even though it was more potent than nordihydroguaiaretic acid (IC₅₀ = 8.5 μM). More recently, Prasada Rao et al.¹²³ have prepared a series of pyrazolo[1,5-a]pyrimidine derivatives and assessed their potency against inhibition of TNF-α with remarkable results.

4.6. Analgesic activity

The series of 6-(2-tolyl-hydrazono)-dihydropyrazolo[1,5-a]pyrimidinones 187a–d (Fig. 26) was evaluated as analgesic agents by a hot plate test in SD rats with a concentration of 15 mg kg⁻¹ for each dose. Diclofenac was used as a reference standard. After two hours, the molecules revealed potent analgesic activities relative to the results of the reference standard (diclofenac, 84.0 ± 12.5%). Compound 187c showed analgesic activity that exceeded that of the reference standard. The order of the activities was as follows: compound 187c (R₁ = CF₃, R₂ = Me, 121.1%) is higher than 187a (R₁ = R₂ = Me, 96.7%), 187b (R₁ = Me, R₂ = Ph, 65.9%), and 187d (R₁ = CF₃, R₂ = Ph, 47.4%). Compound 187b is the only tested sample that showed slight activity after one hour (43.9%), while the other compounds were inactive at first. Compound 187c exhibited anti-inflammatory activity by a carrageenan rat paw edema model.⁷⁵

4.7. Antioxidant activity

The antioxidant activity of 6-(2-tolyl-hydrazono)-dihydropyrazolo[1,5-a]pyrimidinones 187b and 187d (Fig. 26) was evaluated by the ABTS colorimetric assay. The results represented moderate antioxidant activities of both compounds lower than that of the reference standard Trolox (binding activity = 1.0 μM) by five times. Compound 187b (binding activity = 0.21 ± 0.03 μM) showed better activity relative to compound 187d (binding activity = 0.19 ± 0.02 μM). Generally, the compounds can trap the free radicals of ABTS.⁷⁵

4.8. Carboxylesterase activity

The carboxylesterase activity was inspected for compounds 187b and 187d (Fig. 27) against acetylcholinesterase (AChE) of human erythrocytes, butyrylcholinesterase (BChE) of horse serum, and CES (EC) of pig liver. Tacrine and bis(4-nitrophenyl)phosphate were used as reference standards, in which tacrine is inactive against CES. The results, in general, showed that compound 187b (R₁ = CH₃) is inactive, while compound 187d (R₁ = CF₃) inhibited carboxylesterase in a μM concentration range relative to that of bis(4-nitrophenyl)-phosphate. The compounds are inactive against AChE and BChE, with a slight potent activity of compound 187b against BChE, and compound 187d is slightly more active than compound 187b against AChE.⁷⁵

4.9. Antiviral activity

A series of pyrazolopyrimidines 188–197 (Fig. 28) were synthesized in an efficient route to investigate their efficiency as oral respiratory syncytial virus (RSV) fusion inhibitors. Compound 197 was reported as the most effective analog that improves the protein binding of human plasma by adjusting the antiviral potency, permeability, pharmacokinetic properties, and solubility in an aqueous medium that facilitates the formulation of the solution for infants. The key structural changes were the introduction of aminopyrrolidine at the C-5 position of the heterocyclic system. Potential activity was recorded for compound 197 on RSV A and B clinical isolates (n = 75, mean EC₅₀ = 0.43 nM) and revealed a dose-dependent (0–30 mg kg⁻¹) antiviral efficacy in a cotton rat model of RSV infection. Oral treatment with compound 197 was indicated safe in adults and healthy human volunteers tentatively infected with RSV. The results of the high dose verified the potent antiviral effect and reduced disease severity.¹²⁴ In another route, other researchers are attentive to studying the antiviral activity of pyrazolopyrimidines.^125–127

Li et al.¹²⁸ have reported a combination of two or more drugs for highly active antiretroviral therapy and standard of care for HIV-1 infections through optimization of compound 198 at the 2- and 7-positions to give compounds 199 and 200 (Fig. 29). A series of pyrazolopyrimidines was evaluated as allosteric inhibitors for HIV-1 integrase, which bind to the LEDGF/p75 interaction site and disrupt the structure of the integrase multimer that is essential for HIV-1 maturation. Compounds 199 and 200 exhibited strong allosteric inhibition of HIV-1 integrase with low nanomolar antiviral influence in cell culture and encouraging PK characteristics.

Metwally and Abd-Elmoety¹²⁹ have recently utilized the reactivity of pyrazolopyrimidine 201 in the synthesis of arylidenes, hydrazono, and polycyclic systems with the pyrazolopyrimidine motif (Fig. 30). The study was extended to in vitro assessment of the antiviral potency of some compounds against COX-B 4, RVF, VSV, and EMCV viruses. The results indicated that compounds 201, 202c, 202i, 203b and 205 exhibited remarkable potency against the assessed viruses. Additionally, the different assays of antiviral potency demonstrated that compound 202c exhibited a significant inhibitory impact against hepatitis C virus protease (HCV-NS3) (IC₅₀ = 7.33 ± 0.51 μg mL⁻¹) with improved activity compared to compounds 201, 202i, 203b, and 205 and relative to the result of Sovaldi (IC₅₀ = 3.20 ± 1.33 μg mL⁻¹). The indirect assay verified improved inhibitory activity with 31.828% inhibition compared to the direct assay (13.8%). The absorption distribution metabolism excretion findings indicated that the adsorption of compound 201 could be achieved through the gastrointestinal area and is superior to that of the other compounds.

4.10. Anxiolytic effect “antianxiety agents”

The GABA_A-R receptor (γ-aminobutyric acid) is an ionotropic considered as the major neurotransmitter inhibitor in the central nervous system with permeable selectivity for chloride ions and lower for bicarbonate ions. The transmission of the GABAergic system plays a critical role in brain activity regulation during the improvement or disruption of its network.¹³⁰ The affinity of the GABA_A-receptor subtype was assessed in vitro for two synthesized series of pyrazolopyrimidinones 19 and 20. The results showed that compound 20g has anti-anxiety activity analogous to that of diazepam as a standard reference at a dose of 10–30 mg kg⁻¹ (Fig. 31). The activity of compound 20g was tested as an anxiolytic in mice employing the maze test. In this test, a conditional fear occurs by exposing the mice to open spaces individually to study other materials that do not depend solely on the activity of the mice. The results highlighted the effectiveness of compound 20g as an anti-anxiety agent in mice. The results also showed the effectiveness of compound 20g when interacting with subtype receptors of GABA_A (α1, α2, α5) as an attempt to understand and study its biological competence as an anti-anxiety model. Compound 20g was capable of binding the receptors of the α1-subtype receptor at a nanomolar range (K_i = 183 ± 18 nM) and with no affinity with the α2- and α5-subtype receptors.

4.11. Translocator protein affinity

Two series of fluorine-based acetamides 60a–c and 63a–d were assessed in vitro in a binding assay as potent ligands for translocator protein by Tran et al.⁷⁹ The most evaluated compounds exhibited a potent affinity for translocator protein compared to the results of DPA-714. In particular, compound 60a exhibited a better affinity for translocator protein with K_i = 0.94 ± 0.045 nM than the reference standard DPA-714 with remarkable lipophilicity for further in vivo studies on the brain. The radiolysis of compound 60a with [¹⁸F] yielded the isomeric [¹⁸F]60a that was applied for a dynamic PET study in a rat LPS-induced neuroinflammation model. The result of the anti-inflammatory study is comparable to that of [¹⁸F]DPA-714 with a high accumulation of [¹⁸F]60a in microglia and an improved TSPO expression location. Immunohistochemical tests of the dissected brains specified that the uptake location of [¹⁸F]60a in the PET study was reliable, with a positively activated microglia region. This study proved that [¹⁸F]60a could be engaged as a potential PET tracer for detecting neuro-inflammation and possible diagnosis of other diseases, for example, cancers related to TSPO expression (Fig. 32).

Kwon et al.⁹⁴ have prepared fluorinated ligands 70a–c and 71a–c (Fig. 33) with the pyrazolopyrimidine motif and in vitro appraised their proficiency as translocator protein ligands. The compounds demonstrated a nanomolar affinity for translocator protein with high potency. Compound 70a exhibited the most potent affinity for translocator protein and appropriate lipophilicity. Accordingly, compound 70a was chosen for in vivo studies on the brain, and the location of inflammation was detected. The radio-synthesized fluorinated [¹⁸F]70a acts as a favorable PET imaging agent for identifying neuro-inflammation and was found to be appropriate for diagnosing cancers with altered translocator protein expression by dynamic positron emission tomography performances.

4.12. Protein kinase inhibitors

Kosugi et al.¹³¹ have reported the synthesis of pyrazolopyrimidines 208 and 209 through the reactions of the respective aminopyrazoles with β-ketoesters in sodium ethoxide solution as a basic medium. The compounds revealed potent activities as inhibitors for protein kinase 2 (MAPKAP-K2) along with worthy in vitro cellular potency as anti-TNF-α agents and in vivo ability in a mouse model of endotoxin shock. The high potency and selectivity of compound 209 led the authors to synthesize compounds with the same skeleton but different aryl amine substituents (i.e. compounds 208) (Fig. 34). The effect of substituents attached to the C6 position on the improved selectivity over CDK2 can be justified. The pyrazolopyrimidine nucleus developed in vitro cellular strength in LPS-induced TNF-α secretion cell models and a favorable PK profile. The results revealed exceptional in vitro kinase selectivity of (S)-208 in addition to its verified inhibition of HSP27 phosphorylation, a straight substrate of MAPKAP-K2, ensuring that this molecule elicits its influence on TNF-α secretion through inhibition of MAPKAP-K2.

The reaction of 1H-pyrazol-5-amine with 1,3-dimethylpyrimidine-2,4(1H,3H)-dione yielded compounds 210a–k after chlorination and nucleophilic substitution with different amines in multi-step synthetic routes. Compounds 211–213 were prepared from pyrazolo[1,5-a]pyrimidine-3-carboxylic acid under optimized catalytic conditions. Somatic Janus kinase 2 mutations lead to proliferative tumors, and therefore it was necessary to pay attention to the preparation and discovery of Janus kinase 2 inhibitors to be used in the treatment of these disorders. Pyrazolopyrimidines are considered efficient inhibitors for Janus kinase 2 so the activity of compounds of series 210 against Janus kinase 2 led to high selectivity, in contrast to the other Jak family kinases, and worthy pharmacokinetic characteristics. Compound 210j (Fig. 35) verified a time-dependent knockdown of pSTAT5 (IC₅₀ = 7.4 nM), a downstream target of Jak2 (K_i = 0.1 nM).¹³²

Calmodulin-dependent protein kinase II (CaM kinase II or CaMKII) is a serine/threonine-specific protein kinase, which is regulated by the formation of the calcium/calmodulin complex. CAMKII is essential for several signaling cascades, improved activity in numerous cardiac diseases, calcium homeostasis, reuptake in cardiomyocytes (muscle cells containing myofibrils), transportation of chloride in epithelia, selection of positive cytotoxic T cells (a type of white blood cells that inhibit the growth of cancer cells) and activation of CD8 T cells. Aouidate et al.¹³³ reported a series of thirty-six pyrazolopyrimidines as CAMKIIδ kinase inhibitors, in which the compounds are selective inhibitors for CAMKIIδ. The results indicated that the compounds of group 4, i.e. compound 214 (R₁ = NM-Me) (Fig. 36), demonstrated potent inhibitory kinase activities. The SARs (Fig. 36) indicated that six regions A–F in the main skeleton of these compounds are responsible for the inhibitory activities. Therefore, the substituents with hydrophilic nature in medium size, electron-donating groups, and hydrogen acceptors at the E-region enhanced the inhibitory activity. Additionally, the electron-deficient groups between the rings C and D improve the inhibitory activity. The research was also extended for the structure characterization by molecular modeling (3D QSAR), docking studies, and in silico assessment (ADMET). Therefore, the determination coefficient (R²) = 0.676 and leave-one-out cross-validation coefficient (Q²) = 0.956 were calculated.

A series of acetamides 216a–q were prepared through two step-synthesis from the reaction of the corresponding tert-butyl 2-(5-amino-3-(4-methoxyphenyl)-1H-pyrazol-4-yl)acetate with heptane-3,5-dione by heating in ethanol followed by basic hydrolysis in an ethanol/sodium hydroxide solution under microwave irradiation conditions. The second step was accomplished by reactions of the formed carboxylic acid with secondary alkyl amines under catalytic conditions to give compounds 216a–q. Compounds 216a–q (Fig. 37) were evaluated for their translocator protein affinity, in which the affinity was decreased by the branched alkyl chains and bulky alkyl substituents, i.e. compound 216b revealed results of affinity at 0.18 nM, while compound 216h revealed a potency at 59.12 nM. The affinity was released by the incorporation of one phenyl substituent with remarkable implications. Phenyl–ethyl substitution is crucial for potent binding translocator protein affinity with picomolar activity (K_i = 0.28 nM). The symmetric benzyl substituents (compound 216n) decreased the affinity with picomolar activity (K_i = 397.29 nM). The alicyclic substituents (compounds 216o–q) are not superlative for potent binding affinity. The compounds with long-chain carbons (compounds 216d–f) have lipophilic characters, while the non-branched or straight chains have moderate to weak lipophilicity. The phenyl substituents revealed a lipophilicity compromise between long alkyl chain and bulky substituents.¹³⁴

Atypical activation of Bruton's tyrosine kinase (BTK) demonstrates a significant role in the pathogenesis of B-cell lymphomas, signifying that inhibition of BTK is beneficial for the treatment of hematological malignancies. In this route, a series of carboxamides 221 were synthesized by bicyclic ring cyclization through reactions of aminopyrazoles 217 with unsaturated ketones accompanied by acidic hydrolysis of the nitrile group, specific reduction of the pyrimidine ring, and finally, chiral separation (Scheme 25). These compounds were evaluated as selective, irreversible, and potent inhibitors for BTK applying in vitro potency, selectivity, pharmacokinetic (PK), and in vivo pharmacodynamic properties for selected molecules. Compound 221a (zanubrutinib), in which R₁ = OPh and R₂ = 1-acryloylpiperidin-4-yl, exhibited (1) potent activity on BTK and exceptional selectivity over other TEC, EGFR, and Src family kinases, (2) appropriate ADME, admirable in vivo pharmacodynamics in mice and effectiveness in OCI-LY10 xenograft models.¹³⁵

Gopalsamy et al.¹³⁶ identified the basic hydrolysis of the ester group of compound 222 with lithium hydroxide to yield the desired acid, which was coupled with amines under catalytic conditions at room temperature to give the diamide analogs 223, 224, 225a–d, and 226a–d. B-Raf kinase exhibited a precarious protagonist in the Raf–MEK–ERK signaling pathway and its inhibitors might be applied in the treatment of melanomas, colorectal cancer, and other Ras-related human cancers. A series of pyrazolopyrimidines substituted with ethyl carboxylate or their analogous amides 223, 224, 225a–d, and 226a–d were investigated as B-Raf inhibitors by HTS assay (Fig. 38).¹³⁶ Recently, Kurz et al.¹³⁷ have synthesized pyrazolopyrimidine-based macrocyclic skeletons and investigated their selectivity of inhibition for serine/threonine kinase 17A.

4.13. PDE10A inhibitor

The main role of the PDE10A gene is to encode phosphodiesterase-enriched cyclic nucleotides of medium striatum spiny neurons in the brain.¹³⁸ PDEs are hydrolases that degrade intracellular signaling compounds vital to cellular functions such as cAMP and cGMP. Koizumi et al.¹³⁹ have indicated the potency of quinoxalinyl-pyrrolidinyl-based pyrazolopyrimidine 227 as an inhibitor of PDE10A with high selectivity. Applying the rat CAR test, the compound was effective with positive symptoms of schizophrenia. Compound 244 exhibited promising efficiency in rat-dependent anticipation response tests and appropriate pharmacokinetic assets in rats, specifically extraordinary brain penetration, as presented in Fig. 39.

4.14. Phosphodiesterase 10A inhibitors

Raheem et al.¹⁴⁰ have described the synthesis of pyrazolyl-pyridinyl-pyrazolopyrimidine (PyP-1) (229) through two synthetic routes from 5,7-dichloropyrazolo[1,5-a]pyrimidine (228) (Scheme 26). The compound efficiently acted as an inhibitor of PDE10A with subnanomolar potency (PDE10A K_i = 0.23 nM) and exceptional pharmacokinetic (PK) and physicochemical characteristics. The compound's performance as an antipsychotic agent for improved cognition was examined by pharmacodynamic (PD) assays depending on the dose efficiency. The PET enzyme occupancy revealed that PyP-1229 was shown in vivo preclinical target assignation concerning [¹¹C]MK-8193, a novel PDE10A positron emission tomography (PET) tracer.

4.15. Phosphodiesterase (PDE4) inhibitors

Phosphodiesterase (PDE-4) inhibitors are identified as a worthy target for the treatment of asthma and COPD. The reactions of 3-aryl-1H-pyrazol-5-amines with 3-(3,4-dialkoxyphenyl)-3-oxopropanal or its enaminone analog in acetic acid at room temperature produced the individual 2-arylpyrazolopyrimidines 230 in 60–90% yield. The results of the biological evaluation of this series of compounds as PDE-4 inhibitors revealed that high potency was noticed for the vehicle group relative to the control group. Compound 230p reduced the eosinophil peroxidase (EPO) activity by about 50% of the vehicle group. The results indicated that compound 230p (Fig. 40) exhibited a protective effect on the ovalbumin-induced asthma animal model and its valuable effect outcomes comparatively from the suppression of eosinophil infiltration.¹⁴¹

4.16. MALT1 protease inhibitors

Quancard et al.¹⁴² have reported a facile synthesis of a series of pyrazolopyrimidines 231–238 with a substituted urea side chain and optimized the in vivo potency of these compounds as selective inhibitors for allosteric MALT1. The high dose was not effective at first, causing diffuse large B cell lymphoma (DLBCL) in a xenograft model along with shortened half-life and suboptimal strength in whole blood. The amended in vivo potency of these compounds was achieved by masking one hydrogen bond donor of the central urea moiety via intramolecular interaction. Tumor regression was recorded for this compound in a CARD11 mutant ABC-DLBCL lymphoma xenograft model. The subsequent compound 233 (Fig. 41) presented reduced in vitro metabolism along with reduced clearance and increased half-life in rats.

4.17. Potassium modulator channel

Osuma et al.¹⁴³ have reported a strategy for the synthesis of carboxamides 241–243 (Fig. 42) and assessed these compounds as KCNQ channel modulators. Hence, KCNQ has the potency for treating CNS disorders comprising neuropathic pain. Potassium channels consist of membrane-bound proteins, which regulated the flow of potassium ions through the cell membrane. The research has discovered the affinity of the investigated compounds for potassium channels KCNQ2/3. The results of the pyrazolopyrimidine compound investigation revealed potent efficiency in a capsaicin-induced acute, secondary mechanical allodynia model and excellent pharmacokinetic properties relative to the results of the standard retigabine.

4.18. Glutamate receptors

The presynaptic group II metabotropic glutamate receptors (mGlu2 and mGlu3) are mostly expressed in the CNS and signify vital therapeutic targets for several CNS disorders, i.e., anxiety, depression, schizophrenia, pain, addiction, Alzheimer's disease and Parkinson's disease. Two series of carboxamides 244 and 245 were synthesized through multi-step reactions following bicyclic ring construction, nucleophilic substitutions, oxidation, and amidation reactions. These compounds are highly CNS penetrant, with respectable functional potency and selectivity against the other seven mGlu receptor subtypes. Prominently, an analog within this series was the first mGlu2 NAM to indicate an attractive rat in vivo PK profile (low clearance and moderate half-life). Excitingly, these new chemotypes did not permanently reveal an IVIVC, making reliance on in vitro DMPK assays theoretically problematic. While the ideal in vivo mGlu2 NAM did not result from this scaffold-hopping and optimization campaign, advances in CNS penetration coupled with rat PK were appreciated (Fig. 43).¹⁴⁴

In previous research, pyrazolopyrimidines demonstrated remarkable biological characteristics, for instance, as alpha 1 selective ligands,¹⁴⁵ potent active calcium-sensing receptor antagonists,⁸¹ selective CB2 cannabinoid receptor inverse agonists,¹⁴⁶ corticotropin-releasing factor receptor antagonists,¹⁴⁷ selective inhibitors for a tyrosine kinase,¹⁴⁸ B-Raf,¹⁴⁹ Pim-1,^26a mitochondrial branched-chain aminotransferase,¹⁵⁰ CNS penetrant,¹⁵¹ metalloproteinase (MMP-13),¹⁵² IKur,¹⁵³ acyl-CoA: diacylglycerol acyltransferase,¹⁵⁴ allosteric modulators for the hydroxycarboxylic acid receptor (GPR109A),¹⁵⁵ and were used for the treatment of Gaucher disease.¹⁵⁶

5. Conclusion

The current review provided an insight into the medicinal chemistry of heterocycles with a pyrazolopyrimidine core. The cyclization of bicyclic systems was accomplished by cyclocondensation of aminopyrazole derivatives with active reagents such as α,β-unsaturated ketones, β-diketones, enaminones, β-ketoesters, 1,5-diketones, β-ketoaldehydes, enaminonitriles, unsaturated esters, or β-ketonitriles under various conditions of the reactions. The reactivity of substituents linked to the ring carbon enables the synthesis of aryl ethers, diamides by reactions with amines or acid chlorides, synthesis of unsaturated ketones, CH arylation, and synthesis of polycyclic systems and binary heterocycles. In this survey, we highlighted the recent research that reported the various biological profiles of the heterocycles with a pyrazolo[1,5-a]pyrimidine nucleus, including the activity of the compounds such as antimicrobial, antimalarial, antioxidant, etc. The structure–activity relationships studied the effects of the chemical composition, and the effect of substituents on the results of the biological activities were also studied. The nature of the substituents varies; they are either alkyl groups, aryls, amides, esters, sulfonyl groups, arylamines, aryl amides, or heterocyclic systems. The pyrazolo[1,5-a]pyrimidine skeleton was also found as the basic nucleus of heterocycles such as tricyclic and polycyclic systems. Among this class of compounds are those that showed distinct biological activity. Methyl or hydrophilic groups are preferred for the potent efficiency of the tested compounds, while the aryl groups reduce the solubility of these compounds in general, which led to a decrease in their biological potency as expected. The heterocycles with a pyrazolo[1,5-a]pyrimidine skeleton presented notable, varied, and privileged biological attitudes, which provide the possibility for applying these molecules on a large scale for drug design.

6. Future perspective

Recently, some studies depended on the synthesis of compounds similar to some drugs in chemical structure, with the substitution of the substituted groups with others similar to them in cyclic properties. The biological activities of the pyrazolo[3,4-d]pyrimidine isomers such as pyrazolo[4,3-d]pyrimidines have been assessed in several areas, which can also be evaluated for this class of compounds on the same biological pattern. Through the future view of these heterocyclic compounds, we found that this class of compounds is rich in its distinct biological activity, which can be applied in drug discovery, design, and development through clinical applications.

7. Abbreviations

DPPM: 4,7-Dihydropyrazolo[1,5-a]pyrimidine
AMP phosphodiesterase: Adenosine monophosphate phosphodiesterase
KDR kinase: Kinase insert domain receptor
COX-2: Cyclooxygenase-2
HIV-1: Human immunodeficiency virus 1
DPA: 2-(2-(4-Alkoxyphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide
Pim-1: Proto-oncogene serine/threonine-protein kinase
CK2: Casein kinase 2
HCV: Hepatitis C virus
CRF: Chronic renal failure
Serotonin 5-HT: Serotonin or 5-hydroxytryptamine
GABAA: Gamma-aminobutyric acid type A receptors
GABA: Neurotransmitter gamma-aminobutyric acid
PET: Positron emission tomography (a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in metabolic processes; PET scan is a type of test that may be used in cancer treatment)
DDR1: Discoidin domain receptor 1
CAN: Ceric ammonium nitrate
TBAF or n-Bu₄NF: Tetra-n-butylammonium fluoride
HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluoro-phosphate, hexafluorophosphate azabenzotriazole tetramethyl uronium
DIBAL-H: Diisobutylaluminium hydride
DavePhos: 2-Dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl
DES: Deep eutectic solvent
gla. AcOH: Glacial acetic acid
MIC: Minimum inhibitory concentration
SAR: Structure–activity relationship
POCl₃: Phosphoryl chloride
DHODH: Dihydroorotate dehydrogenase
BGM: Buffalo green monkey cells
A549: Lung cancer
MDA-MB-231: Breast cancer
DU-145: Prostate cancer
HEK293: Human embryonic kidney cells
SiHa: Hypertriploid human cell line
HeLa: Human cervical cancer cell line
IC₅₀: Half-maximal inhibitory concentration
EDCI: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (activates the carboxylic group for coupling reactions with amines)
HOBt: Hydroxybenzotriazole (enables the formation of amides)
MTT: 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT assay is a colorimetric assay for assessing cell metabolic activity)
MCF-7: Human breast cancer
PC3: Human prostate cancer
PCa: Prostate cancer
AR: Androgen receptor
HepG-2: Human hepatocellular carcinoma
HCT-116: Colorectal adenocarcinoma
Colo-205: Colon cancer
CHO K1: Mammalian cell line used for mass production of therapeutic proteins
NO: Nitric oxide
SD: Sprague Dawley rat
AChE: Acetylcholinesterase
BChE: Butyrylcholinesterase
RSV: Respiratory syncytial virus
EC₅₀: Half maximal effective concentration
TSPO: Translocator protein
[¹⁸F]DPA-714: N,N-Diethyl-2-(2-(4-(2[¹⁸F]-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)-acetamide
TNF alpha: Tumour necrosis factor alpha
QSAR: Quantitative structure–activity relationship
PDE: Phosphodiesterases
cAMP: Cyclic adenosine monophosphate
cGMP: Cyclic guanosine monophosphate
EPO: Eosinophil peroxidase (an enzyme found within the eosinophil granulocytes, innate immune cells of humans and mammals)
CNS: Central nervous system
COX-B 4: Coxsackie virus B 4
RVF: Rift Valley fever
VSV: Vesicular stomatitis virus
EMCV: Encephalomyocarditis virus

Conflicts of interest

There is no conflict of interest to declare.

Supplementary Material

Biographies

Biography

Dr. Mohamed M. Hammouda was born in Mansoura, Egypt, in 1983. He received his B.Sc. in 2004 and his M.Sc. in 2008 from the Faculty of Science, Mansoura University, Mansoura, Egypt. He obtained his Ph.D. in organic chemistry in 2013 from the Faculty of Science, Mansoura University, Egypt (Ph.D. thesis: Synthesis and Reactions of some New Isatin Mannich Bases and Related Compounds of Expected Biological Activity). In 2013 he joined the Erasmus Mundus postdoctoral fellowship, Laboratory of Organic and Bio-Organic Synthesis, Ghent University, Belgium. His postdoctoral research is focused on the development of a new type of chiral catalyst for a wide variety of enantioselective reactions. In 2017 he joined the Department of Chemistry, Faculty of Science, Mansoura University, as a Lecturer of organic chemistry (“Synthesis of nitrogen-containing compounds for antioxidant activity”). In 2021 he joined the Department of Chemistry, College of Science and Humanities in Al-Kharj, Prince Sattam Bin Abdulaziz University, Saudi Arabia, as an Assistant Professor of organic chemistry.

Biography

Professor Hatem E. Gaffer is a Professor (since 2016) in the Department of Dyeing and Printing, Textile Division, National Research Centre, Egypt. He received his B.Sc. in chemistry in 1992, his M.Sc. in 1998 and his Ph.D. in organic chemistry in 2005 from the Faculty of Science, Mansoura University, Egypt. His research interest covers the synthesis of heterocycles, novel azo disperse dyes, and dyeing textiles. His specialized area of interest is the organic synthesis, dye application, and biological activity of organic compounds. He received the Pioneer Award in 2014. He was a visiting professor at North Carolina State University in 2017.

Biography

Dr. Khaled M. Elattar was born in Menyet Samannoud, Aga, El-dakahlia, Egypt (1979). He received his B.Sc. in 2002 from the Faculty of Science, Mansoura University, Egypt, and his M.Sc. in 2006 from the Faculty of Science, Benha University, Benha, Egypt. He obtained his Ph.D. in organic chemistry in 2011 from the Faculty of Science, Mansoura University, Egypt (Ph.D. supervisors: Prof. A. A. Fadda and Prof. A. S. Fouda). He was a Lecturer in Organic Chemistry at the Faculty of Education of the Sert University, Sert, Libya, from 2012 to 2015. He is a member of the Egyptian Chemical Society. He is a reviewer for some scientific international journals. His main research interests are in the field of organic synthesis, the synthesis of heterocyclic compounds of pharmaceutical interest, and medicinal chemistry. He joined the editorial board of OA Journal – Pharmaceutics in 2018 (https://oa.enpress-publisher.com/index.php/Pha/about/editorialTeam). Currently, he is in the editorial board of the following journals: Journal of Applied Science, Asian Journal of Textile, Asian Journal of Applied Science, International Journal of Chemical Technology, and Current Research in Chemistry. Recently, he joined the Asian Council of Science Editors (ACSE).

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PERMALINK

Insights into the medicinal chemistry of heterocycles integrated with a pyrazolo[1,5-a]pyrimidine scaffold

Mohamed M Hammouda

Hatem E Gaffer

Khaled M Elattar

Abstract

1. Introduction

Fig. 1. Synthetic drugs incorporated with a pyrazolopyrimidine core.

2. Model synthetic strategies

2.1. Bicyclic ring construction from β-diketones

Scheme 1. Synthesis of 6-(2-tolyl-hydrazono)-dihydropyrazolo[1,5-a]pyrimidinones.

Scheme 2. Synthesis of pyrazolopyrimidine-5-carboxylic acids.

Scheme 3. Synthesis of 3,6-disubstituted pyrazolopyrimidinones.

Scheme 4. Synthesis of substituted pyrazolopyrimidines.

Scheme 5. Synthesis of bicyclic systems from β-diketones.

2.2. Bicyclic ring construction from α,β-unsaturated ketones

Scheme 6. Synthesis of bicyclic systems from unsaturated ketone.

2.3. Bicyclic ring construction from α,β-unsaturated nitriles

Scheme 7. Synthesis of bicyclic systems from unsaturated nitriles.

2.4. Bicyclic ring construction from enaminones

Scheme 8. Reactions of aminopyrazoles with enaminones.

Scheme 9. Synthesis of bicyclic pyrazolo[1,5-a]pyrimidines under ultrasonic irradiation conditions.

3. Reactivity

3.1. Reactivity of substituents linked to ring carbon

3.1.1. Synthesis of aryl ethers

Scheme 10. Synthesis of fluorine-based pyrazolopyrimidinyl-N,N-disubstituted-acetamides.

Scheme 11. Synthesis of pyrazolopyrimidinyl-N,N-alkyl-acetamides.

3.1.2. Synthesis of diamides

Scheme 12. Synthesis of diamide derivatives.

Scheme 13. Reactions of N-alkyliodide salts with methyl amine.

3.1.3. Synthesis of unsaturated ketones

Scheme 14. Synthesis of chalcone-based pyrazolopyrimidines.

3.1.4. CH-arylation reactions

Scheme 15. Arylation of ethyl acetates.

3.2. Reactions involving substituents attached to ring nitrogen atoms

Scheme 16. Synthesis of N-alkyliodide salts.

3.3. Synthesis and reactivity of polycyclic systems

Scheme 17. Amination and synthesis of tetracyclic systems.

Scheme 18. Synthesis of tricyclic pyrazolopyrimidopyrimidinones.

3.4. Synthesis of binary heterocycles

Scheme 19. Synthesis of binary 1H-pyrazoles and bicyclic pyrazolo[3,4-d]pyrimidinones.

Scheme 20. Reactions of amines with anhydrides and 3-acetyldihydro-furan-2(3H)-one.

4. Biological characteristics

4.1. Antimicrobial activity

Scheme 21. Synthesis of pyrazolopyrimidine 128.

Fig. 2. SARs and antimicrobial results of the pyrazolopyrimidinones and pyrazolopyrimidines.

Fig. 3. SARs of potent bicyclic and binary pyrazolopyrimidines.

Fig. 4. SARs of carboxamide analogs as potent antimicrobial agents.

Fig. 5. SARs of bicyclic heterocycles as antibacterial agents.

Fig. 6. The SARs of antibacterial pyrazolopyrimidines.

Fig. 7. The SARs of pyrazolopyrimidines as potent antimicrobial agents.

Fig. 8. The SARs of pyrazolopyrimidines as antimicrobial and anticancer agents.

Scheme 22. Simple synthesis of potent antibacterial agents.

Fig. 9. The structures of substituted bicyclic heterocycles as potent antimicrobial agents.

4.2. Antimalarial activity

Scheme 23. Synthesis of pyrazolopyrimidines.

4.3. Antiproliferative activity

Fig. 10. The SARs of the most potent cytotoxic agents.

4.4. Cytotoxic activity

Fig. 11. The SARs of carboxamides as potent cytotoxic agents.

Fig. 12. The SARs of carboxamides as potent anticancer agents.

Scheme 24. SARs of diamides as potent cytotoxic agents.

Fig. 13. The SARs of diamides of pyrazolopyrimidines as cytotoxic agents.

Fig. 14. The SARs of the most effective cytotoxic agents.

Fig. 15. The SARs of dialkyl phosphonates as anticancer agents.

Fig. 16. SARs of bicyclic and tricyclic pyrazolo[1,5-a]quinazoline-3-carboxamides as potent cytotoxic agents.

Fig. 17. The SARs of anticancer pyrazolopyrimidines.

Fig. 18. SARs of the potent anticancer agents for prostate cancer cells.

Fig. 19. SARs of bicyclic pyrazolopyrimidines as potent cytotoxic agents.

Fig. 20. The SARs of cytotoxic and anti-inflammatory agents.

Fig. 21. The SARs of potent anti-cancer and anti-inflammatory agents.

Fig. 22. The structures and SARs of bicyclic pyrazolopyrimidines as potential antitumor agents.

Fig. 23. The structures and SARs of bicyclic-based heterocycles as potential cytotoxic agents.

Fig. 24. The structures and SARs of bicyclic heterocycles as cytotoxic agents.

4.5. Anti-inflammatory activity

Fig. 25. The structures and SARs of potential anti-inflammatory agents.

4.6. Analgesic activity

Fig. 26. The SARs of dihydropyrazolo[1,5-a]pyrimidinones as potent analgesic and antioxidant agents.

4.7. Antioxidant activity

4.8. Carboxylesterase activity