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. 2025 Oct 6;10(40):46248–46271. doi: 10.1021/acsomega.5c04880

Recent Progress in the Synthesis, Functionalization, and Biological Outlook of Pyrimidines

Glanish Jude Martis †, Praveen S Mugali ‡, Santosh L Gaonkar †,*
PMCID: PMC12529397  PMID: 41114227

Abstract

Pyrimidine-containing heterocyclic molecules are highly important in medicinal chemistry because of their versatile biological activities and their potential for structural modification. These scaffolds have consistently attracted the attention of chemists and biologists alike and serve as key building blocks in the design and development of bioactive compounds. Recent advances in pyrimidine chemistryincluding novel synthetic methodologies, named reactions, catalytic strategies, and functionalization techniqueshave further expanded their applicability. The biological importance of pyrimidine derivatives has been instrumental in the development of several commercially available drugs in recent years. Given the ongoing global research in this area, there is a clear need to review and highlight recent developments in a systematic manner. This review not only provides insights into current trends but also serves as a valuable resource for researchers in the pharmaceutical industry and academic institutions engaged in early-stage drug discovery efforts.

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1. Introduction

Owing to their versatile behavior and nature, heterocyclic molecules are widely attractive across all fields of chemistry, which makes them special. Likewise, pyrimidine has been a core part of genetic research since the 1930s. The most profound genetic materials, namely DNA and RNA, contain purines and pyrimidines as nitrogenous bases (Figure ). − Among these, thymine, uracil, and cytosine have pyrimidine cores with several biologically important features, highlighting their interest in the fields of chemical biology and medicinal chemistry. −

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Pyrimidines in DNA and RNA.

However, synthetic organic chemistry has been a boon for the development of all the drugs that are commercially available today in global pharmacies. , Similarly, pyrimidine chemistry has furnished groundbreaking results that have aided in drug design and development. − One of the familiar and popular reactions proposed by Pietro Biginelli has emerged as an effective method with several advantages, such as diverse reaction optimizations. The very important factor is their modifications and improvements, which lead to the production of new lead molecules. − Pyrimidine–-tetrahydropyrimidinethione hybrids produced via the Biginelli reaction have been used as an effective antimycobacterial agents with promising results.

Several metal-catalyzed reactions are instrumental in the synthesis of pyrimidines. The selection, improvisation, and incorporation of these compounds are important for obtaining target molecules in significant yields; hence, recent advances and research on pyrimidine chemistry are needed. Likewise, microwave- and ultrasound-assisted organic synthesis have been widely used in recent years. − Their utility has been remarkable in the production of several distinguished heterocyclic scaffolds, and their scale-up reactions and process chemistry remain challenging.

In recent years, extensive research has been carried out on the direct functionalization of heterocyclic compounds, such as C–H and N–H. These functionalization processes involve different molecules, and their productivity is high. − The biology of pyrimidines is being studied in all sectors of education and research, as it is related to genetic approaches and human life. Various researchers working on pyrimidine molecules have pushed themselves to produce compounds with therapeutic potential, such as antiviral, , anticancer, , anti-inflammatory, , and antioxidant agents. , Apart from these, pyrimidine-containing heterocyclic scaffolds have demonstrated their utility as anti-HIV, antihypertension, and antimalarial agents. Nowadays, pyrimidines are used for the detection of SARS-CoV-2 via triplex formation of modified bis-pyrimidine core structures. Multifaceted studies are being carried out beyond the biology and synthetic fields of pyrimidine, taking them to newer dimensions. In our previous work, we discussed the latest developments in the biology of pyrimidines in the above-mentioned areas, along with a few synthetic methods (Figure ).

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Recently developed pyrimidine-containing biologically active agents.

Since the versatility of pyrimidine has grown to greater heights, the aim or target of this review is to focus on the latest progress in the synthetic chemistry and biological importance of pyrimidine-containing heterocyclic hybrids. With this intent, we present the recent developments in the synthetic chemistry of pyrimidines involving Biginelli reactions, metal-catalyzed reactions, microwave- and ultrasound-promoted syntheses, and different direct functionalization reactions for the development of various analogues of therapeutic importance. In addition to their synthetic protocols, the latest results concerning antimicrobial, antitubercular, and antidiabetic activities have been included, which will direct the scope of this article to drug design and development. The detailed discussions and overviews help synthetic and medicinal chemists to dive deep into pyrimidine-containing heterocyclic chemistry. Therefore, this article benefits researchers working in both academic and industrial areas.

2. Synthetic Developments of Pyrimidines

2.1. Biginelli Reactions

Biginelli reactions have been instrumental in producing several interesting dihydropyrimidines via an acid-catalyzed three-component reaction between an aldehyde, β-ketoester, and various urea derivatives. This has been a classic approach for producing biologically active pyrimidines as well. Here, we discuss the latest progress in pyrimidine-related synthetic chemistry via Biginelli reactions under different reaction conditions.

Zohny et al. used the Biginelli reaction for the synthesis of pyrimidine derivatives 8, which are suspected to be promising calcium channel blockers for lowering human blood pressure, thereby acting as antihypertensive agents. By incorporating aromatic aldehydes, several optimizations were carried out, among which 1,3-diphenyl-1H-pyrazole-4-carbaldehyde 3 results in active calcium channel blockers with pyrimidine core structures. Moreover, their synthesis started with the reactions of thiourea 1, ethyl acetoacetate 2, and the aforementioned aryl aldehyde 3 to yield the corresponding pyrimidine ester 4. This ester was then hydrolyzed via alcoholic NaOH to acid 5 and transformed into the chloro derivative 6 via thionyl chloride. As the final step, the resulting chloro derivatives were condensed with three different aromatic amines 7 namely, aniline, p-toluidine and p-nitroaniline to yield the desired final compounds 8 (Scheme ).

1. Synthesis of Pyrimidine–Pyrazole Hybrids 8 via the Biginelli Reaction.

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Venkatesh et al. constructed [1,3]­dioxino­[4,5-d]­pyrimidine derivative 12 via the Biginelli reaction involving Meldrum’s acid 9, indole-3-carbaldehyde 10, and urea 11 in ethanol. The most interesting aspect of this reaction was its completion within 20 min under reflux, facilitated by ceric ammonium nitrate (CAN). The mechanism involves the formation of the Schiff base intermediate and its reaction with Meldrum’s acid 9 as the reactive methylene compound, triggering the formation of pyrimidines with the loss of a water molecule. The product held its own significance as an antitubercular agent tested against the Mycobacterium tuberculosis H37RV strain, with the lowest binding energy of −9.3 kcal/mol (Scheme ).

2. Synthesis of [1,3]­Dioxino­[4,5-d]­pyrimidine Derivative 12 .

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Krishnan et al. evaluated Biginelli pyrimidine products 14 and 16 for their anticancer activity against the A549, HT29, and HepG2 cell lines. By reacting urea 11 and ethyl acetoacetate 2 with two different aromatic aldehydes, namely 4-chlorobenzaldehyde 13 and 4-methoxybenzaldehyde 15, to yield the respective dihydropyrimidines 14 and 16. For these reactions, several optimization conditions were tested and screened with different catalysts, such as p-TSA, CAN, oxalic acid, and Cu­(OAc)2, which produced low to moderate yields, whereas TBAB resulted in the Knoevenagel condensed product. Finally, the best yields were obtained using imidazole hydrochloride as the efficient catalyst for this particular reaction. The dihydropyrimidine products were effective as anticancer molecules, showing a close resemblance to the standard drug doxorubicin (Scheme ).

3. Synthesis of Dihydropyrimidines 14 and 16 via the Biginelli Reaction.

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Jadhav and coworkers provided rapid access to the Biginelli reaction to construct 1,2,3,4-tetrahydropyrimidines 23 at room temperature via the use of diisopropyl ethylammonium acetate 19 as an efficient ionic liquid catalyst. In addition to this ionic liquid catalyst, several attempts have been made with different catalysts, such as p-TSA, sodium dodecyl sulfate (SDS), and poly­(ethylene glycol) 400, which are moderate in action, whereas the utility of phase transfer catalysts (PTCs) is sluggish. When reacted with ethyl-2-cyanoacetate 21 and amines 22, aromatic aldehyde 20 furnished final products 23 in excellent yields of up to 98% (Scheme ).

4. Biginelli Reaction for the Synthesis of 1,2,3,4-Tetrahydropyrimidines 23 .

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2.2. Metal-Catalyzed Reactions

In recent years, metal-catalyzed reactions have paved many routes for the efficient synthesis of interesting heterocyclic compounds. Among them, several works on pyrimidine have dragged greater attention for successfully executing complicated and complex reactions. Organic catalysis using Zn/Pd and Cu catalysts has left an indelible mark in the field of synthetic chemistry. Their role in accelerating the reaction has been significant, with various reaction optimizations. Here, we discuss the Zn-, Pd-, and Cu-catalyzed reactions, which yield many important pyrimidine core molecules.

2.2.1. Zinc/Palladium-Catalyzed Reactions

An amino acid complex linked with zinc metal triggered the synthesis of novel pyrimidines 28 in an aqueous medium. The Zn­(l-proline)2 catalyst was prepared by mixing l-proline and triethylamine in ethanol and stirring for 20 min at room temperature. Furthermore, Zn­(AcO)2·6H2O was added dropwise to a small amount of water with continuous stirring at RT for 5–7 h. The white Zn-linked amino acid complex was filtered and dried under a vacuum for 4 h and employed as an efficient catalyst for the synthesis of pyrimidines from guanidines 27. For the synthesis of the precursor, aromatic aldehydes 24 were reacted with acetophenones 25 in a mixture of water and ethanol to yield chalcone intermediates 26, and their treatment with different benzoguanidines 27 led to the formation of target pyrimidines 28 (80–97% yield) facilitated by the Zn-complex catalyst in an aqueous medium (Scheme ).

5. Zn Complex-Catalyzed Synthesis of Pyrimidines 28 .

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The dehydrogenative synthesis of 2,4,6-triphenyl pyrimidines 32 was developed using Pd@Pt core–shell nanoparticles capped by polyvinylpyrrolidone (PVP) and supported by carbon; all of these nanoparticles were maintained and prepared in a flow reactor as a continuous process. This catalyst accelerated the reaction between primary 30, secondary alcohols 29, and amidines 31 in potassium tert-butoxide, which is the optimized base for the reaction. This synthesis is a part of a cascade of reactions involving the oxidation of alcohols to aldehydes and ketones and their cross-aldol condensation to give α, β-unsaturated ketone intermediates, whose reaction with amidines leads to the formation of pyrimidines through the C–N coupling reaction pathway in isolated yields of 65–85% (Scheme ).

6. Palladium-Catalyzed ehydrogenativeDehydrogenation Synthesis of 2,4,6-Triphenyl Pyrimidines 32 .

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Palladium-catalyzed isocyanide 34 insertion into 2H-azirines 33 led to the formation of polysubstituted pyrimidines 35 via the formation of one C–C and two C–N bonds with promising functional group tolerance. Palladium acetate and triphenylphosphine govern the reaction mechanism involving four main steps commencing with the oxidative addition of the azirine to the Pd complex, leading to the opening of the three-membered ring, followed by the isocyanide and repeating azirine insertions, which further led to ring expansion. Later, the reductive elimination and hydrolysis yield the target compounds with yields ranging from 0 to 98% (Scheme ).

7. Palladium-Catalyzed Synthesis of Polysubstituted Pyrimidines 35 .

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2.2.2. Copper-Catalyzed Synthesis

Tiwari et al. synthesized pyrazolopyrimidine-linked triazole glycohybrids 41 starting from diverse β-keto esters 36 obtained by the esterification of different acetophenones using diethyl carbonate. The presence of electron-withdrawing groups such as -trifluoromethyl and -fluoro in the aryl ring contributed to a lower yield, whereas electron-donating groups such as -methyl and -methoxy favored good yields. Pyrazolopyrimidine 38 was first obtained through a reflux reaction between β-keto esters 36 and 3-amino pyrazole 37 in acetic acid for 12–14 hours, yielding satisfactory results. The corresponding alkyne-pyrazolopyrimidines 39 were synthesized using propargyl bromide to facilitate an upcoming click reaction with azido glucoside 40 using copper sulfate/sodium ascorbate, resulting in their respective triazole-linked glycohybrids 41 in very high yields under microwave conditions (Scheme ).

8. Synthesis of Pyrazolopyrimidine-Linked Triazole Glycohybrids 41 .

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Wang et al. annulated α, β-unsaturated ketoximes in a [4+2] fashion with activated nitriles to construct different 2,4,6-trisubstituted pyrimidines 44. The reaction of chalcone-derived oxime acetates 42 with malononitrile 43, catalyzed by Cu­(MeCN)4PF6 in dimethylacetamide (DMA) and 1,4-dioxane at a 1:9 ratio at 110 °C for 12 h, afforded the target compounds in an average yield of 82%. Several reaction conditions were examined, and after thorough investigation, the above reaction conditions were determined to be the most favorable for achieving promising yields. Apart from such optimizations, three different radical inhibitors, namely TEMPO, BHT, and DPE were utilized to check the performance of the reaction and produced compounds at 76–78% yields, whereas without them, the yield was slightly better (80%) (Scheme ).

9. Copper-Catalyzed Synthesis of 2,4,6-Trisubstituted Pyrimidines 44 via [4+2] Annulation.

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Zarren et al. synthesized anthraquinone-based pyrimidine analogues 49 for the development of potent probes with antioxidant activity. The precursors anthraquinone 47 and pyrimidine derivatives 48 were synthesized in two separate parts. First, phthalic anhydride 45 was reacted with substituted benzenes 46 in the presence of alum at room temperature, followed by treatment with concentrated HCl to yield the precursor anthraquinone 47. Second, substituted aromatic aldehydes 24 were transformed into pyrimidines 48 via their reactions with urea 11 and ethyl acetoacetate 2. These two substrates were reacted in the presence of copper chloride, cupric oxide, and methanol to yield four different anthraquinone-pyrimidine probes 49 (Scheme ).

10. Copper-Catalyzed Synthesis of Anthraquinone-Based Pyrimidine Analogues 49 .

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Putta et al. developed a copper-catalyzed dual synthon approach for the synthesis of pyrimidines 52 via the difunctionalization of tertiary alkylamines. In this method, tertiary alkylamines such as N,N,N′,N′-tetraethylethylenediamine (TEEDA) 51 act as efficient dual C2 synthons. In this two-component synthesis of pyrimidine, amidine hydrochloride 50 was reacted with TEEDA 51 in the presence of CuCl2 at 90 °C under aerobic conditions for 48 h. Various experiments were carried out to select superior catalysts, and finally CuCl2 exhibited the best performance. 1,4-Dioxane serves as the ideal solvent for the reaction, as DMSO, a one-carbon donor in several organic reactions, could not afford products under the above reaction conditions (Scheme ).

11. Copper-Catalyzed Difunctionalization of Tertiary Alkylamines for the Synthesis of Pyrimidines 52 .

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Li et al. constructed (E)-2,4-diaryl-6-styrylpyrimidines 55 from distyrylketones 53 and benzamidines 54 through a CuBr-catalyzed reaction in the presence of 2,2′-bypridine and DMSO at 100 °C for 12 h in an oil bath. The advantages of this reaction include the use of low-cost catalysts, easily available substrates, wide functional group tolerance, high atom economy, and the resulting products in yields of up to 98% (Scheme ).

12. Synthesis of (E)-2,4-Diaryl-6-styrylpyrimidines 55 .

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2.3. Microwave/Ultrasound-Assisted Synthesis

In recent years, microwave and ultrasound techniques have been widely used due to their remarkable properties and the execution of reactions with several merits. Thus, their principles are a must-learn aspect for every organic chemist who is on the verge of excelling in the field of synthetic organic chemistry. The major advantages of these techniques include reduced time consumption, high-yield products, minimal use of solvents, etc. These merits have enabled various researchers to undertake pyrimidine chemistry under microwave/ultrasound principles, as discussed below.

Trivedi et al. synthesized pyrimido­[4,5-d]­pyrimidines 59 from barbituric acid 56, aromatic aldehydes 57, and amines 22 under microwave conditions for 5 min in the presence of an iodine solution prepared by dissolving iodine in potassium iodide. An additional 50 mL of water was added before the reaction was placed into a microwave reactor at 640 W. The same reaction was carried out under ultrasound, and it was found that the reaction duration was longer with a lower yield compared to microwave irradiation (Scheme ).

13. Microwave-Assisted Synthesis of Pyrimido­[4,5-d]­pyrimidines 59 .

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Panneerselvam and Mandhadi constructed thiosemicarbazide derivatives of pyrimidine 69 via a microwave synthesizer from the substrate aromatic aldehydes 60, ethyl-2-cyanoacetate 21, and guanidine hydrochloride 61 to yield the intermediate 2-amino-4-hydroxy-6-(substituted benzyl)­pyrimidine-5-carboxamide 62. This intermediate 62 was then esterified using ethyl-2-bromoacetate 63 and propanone 64 to give ethyl-2-((2-amino-5-carbamoyl-6-(substituted benzyl) pyrimidin-4-yl)­oxy)­acetate 65, whose condensation with thiosemicarbazide 66 led to the formation of prefinal compounds 2-amino-4-(2-[2-carbamothioylhydrazinyl]-2-oxoethoxy)-6-(substituted benzyl)­pyrimidine-5-carboxamides 67. In the final step, it was treated with acetaldehyde 68 to give the final compounds 69. All the reactions were carried out under microwave irradiation and furnished products in 3–5 min with a yield of 63–82% (Scheme ).

14. Microwave-Assisted Synthesis of Thiosemicarbazide Derivatives of Pyrimidine 69 .

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Alizadeh et al. designed pyrrole-fused pyrimidine 75 via an ultrasound method involving the reaction between arylglyoxals 70 and malononitrile 43 to yield 2-(2-oxo-2-arylethylidene) malononitrile 71 as the first precursor for the final reaction. On the other hand, the second precursors, viz., ketene aminals 74, were prepared from 1,1-bis­(methylthio)-2-nitroethylene 72 and diamines 73 with 20 kHz ultrasonic radiation. The precursors were then combined to give pyrrole-fused pyrimidine analogues 75 with 39–95% (Scheme ).

15. Ultrasound-Promoted Synthesis of Pyrrole-Fused Pyrimidine Analogues 75 .

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Kerru et al. employed an ultrasound-assisted synthetic protocol for the synthesis of benzothiazole­[3,2-a]­pyrimidine derivatives 78 via MCR involving 2-aminobenzothiazole 76, aromatic aldehydes 57, and substituted nitriles 77 in the presence of fused ammonia and ethanol at room temperature. The most fascinating factor is their extremely well-established yields in all the cases of the reactions, which are above 94% (Scheme ).

16. Ultrasound-Assisted Synthesis of Benzothiazole­[3,2-a]­pyrimidine Derivatives 78 .

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Thavasianandam Seenivasan et al. investigated the substrate scope of CF3–ynones 79 for the synthesis of polyfluoro-pyrimido [1,2-a]­benzimidazole analogues 81 via an ultrasound-assisted technique. First, various classes of CF3–ynones 79 were treated with 2-aminobenzimidazole 80 and reacted in an ultrasonicator in a neat, open-air atmosphere for an hour to yield the final compounds 81. This reaction was facilitated without the use of solvents or metals and produced compounds with high functional group tolerance, with yields ranging from 28 to 95% (Scheme ).

17. Ultrasound-Mediated Synthesis of Polyfluoro-pyrimido [1,2-a]­benzimidazole Analogues 81 .

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3. Functionalization of Pyrimidines

Interestingly, several attempts have been made to modify the pyrimidine nucleus with different functional groups in recent years. By making such modifications, many doors could open for the production of medicinally important pyrimidine-containing scaffolds. Functionalization can be achieved by replacing one hydrogen atom from the pyrimidine core with a different functional group or substituent. Thus, we discuss recent developments in the functionalization of pyrimidine heterocycles.

Das et al. carried out remote C–H functionalization of 2-aminopyrimidines 82 via a palladium-catalyzed reaction. Arylation of 2-aminopyrimidine core 82 with aryl halides 83 emerged as a highly regioselective approach. Moreover, it displayed good tolerance to different aryl halides and produced functionalized products 84 in satisfactory yields (Scheme ).

18. Palladium-Catalyzed C–H Functionalization of 2-Aminopyrimidines 82 .

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Zhang et al. developed a unique regioselective approach enabling palladium-catalyzed, sodium iodide-promoted C–H diacetoxylation of pyrrolo­[2,3-d]­pyrimidine derivatives 85. This diacetoxylation was performed exclusively at the C-4 phenyl ring and the C-5 position of the pyrrole ring. Various electron-donating groups afforded products 86 in good yields (Scheme ).

19. Palladium-Catalyzed, NaI-Promoted C–H Diacetoxylation of Pyrrolo­[2,3-d]­pyrimidine Derivatives 85 .

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Muzychka et al. synthesized triphenylphosphonium-functionalized pyrimidines 90–91 for antibiofilm activity. Methyl [3,5-dibromo-4-(2-bromomethoxy)­phenyl]­acetate 87 was treated with phosphoranylidenepyrimidines 88 and 89 to yield the target triphenylphosphonium-containing pyrimidine derivatives 90 and 91 under reflux with acetonitrile (Scheme ).

20. Synthesis of Triphenylphosphonium Functionalized Pyrimidines 90–91 .

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Pilli et al. functionalized 2,4-dichloropyrimidine intermediate 97 synthesized from the Wittig reaction/hydrogenation procedure of salicylaldehyde 92, yielding tertiary butyl ester 94, whose SN2 reaction with bromopropanol 95 was followed by a Mitsunobu reaction involving diisopropyl azodicarboxylate (DIAD), triphenylphosphine, and 5-hydroxy-2,4-dicholoropyrimidine 97. Later, Negishi and Sonogashira reactions were performed on this 2,4-dichloropyrimidine to obtain highly functionalized products (Scheme ).

21. Synthesis and Functionalization of 2,4-Dichloropyrimidine Intermediate 97 .

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4. Biology of Pyrimidines

Pyrimidine is a biologically important and versatile heterocyclic compound. By experimenting with several reactions involving pyrimidine molecules, numerous drugs are now commercially available, which help in curing various deadly diseases and inhibit transmissions from pathogens. The medicinal importance of pyrimidines has been discussed in this section, which aims to provide new insights into the domain of pharmaceutical chemistry.

4.1. Antimicrobial Activity

Antimicrobial activity includes antibacterial and antifungal effects. Thus, these activities help pharmacists and chemists understand the chemical and medicinal effects of treating infections. Several drug molecules are available in the commercial sector, such as trimethoprim, cyprodinil, and sulfadiazine, as shown in Table .

1. Pyrimidine-Containing Antimicrobia Drugs.

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Ibrahim et al. produced novel heteroannulated chromene-pyrido-thiazolo-pyrimidines from an aldehyde derivative in DMF/DBU and tested their antibacterial activity against Gram-positive (Staphylococcus aureus and Bacillus subtilis) and Gram-negative (Salmonella typhimurium and Escherichia coli) strains. Compared with chloramphenicol, cycloheximide, and cephalothin, which are standard reference drugs, compounds 101–103 showed prominent activity against both Gram-positive and Gram-negative bacteria. The inhibition values were 1000 and 500 μg/mL, respectively. Compounds 104–105 showed high antibacterial activity against Gram-positive bacteria only. They also investigated the compounds for their antifungal activity against Aspergillus fumigatus and reported that compounds 99–106 displayed high activity. Therefore, heteroannulation profoundly increased the antibacterial and antifungal activity (Scheme ).

22. Synthesis of Antibacterial Compounds 100–106 .

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Alamshany and Nossier synthesized new thiazole-linked pyrimidine derivatives and investigated their antimicrobial activity against Staphylococcus aureus, Streptococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Saccharomyces cerevisiae, and Candida albicans. Except for C. albicans, compounds 108/109 effectively inhibited all of the bacteria and yeast. The minimal inhibitory concentrations (MICs) of compounds 108/109 were 0.20 ± 0.02/0.25 ± 0.01 (S. aureus), 0.38 ± 0.06/0.45 ± 0.01 (S. faecalis), 0.49 ± 0.03/0.44 ± 0.05 (E. coli), 0.41 ± 0.05/0.45 ± 0.03 (K. pneumoniae), and 0.32 ± 0.04/0.42 ± 0.06 (S. cerevisiae). The zones of inhibition were measured (in mm) for compounds 108/109 against all the microbial species and were reported to be 30 ± 0.75/29 ± 0.81 (S. aureus), 28 ± 0.47/25 ± 0.14 (S. faecalis), 25 ± 0.37/23 ± 0.18 (E. coli), 26 ± 0.18/25 ± 0.65 (K. pneumoniae), and 28 ± 0.29/26 ± 0.40 (S. cerevisiae), respectively. Chloramphenicol and ketoconazole were used as the standard drugs for evaluation (Scheme ).

23. Synthesis of Thiazole-Linked Pyrimidine Derivatives 108–109 .

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Badiger and Kamanna developed a greener approach for synthesizing pyranopyrimidine derivatives via the use of the eco-friendly catalyst water extract of pomegranate peel ash (WEPPA) under microwave conditions and subjected this approach to antimicrobial studies against Bacillus, E. coli, Pseudomonas, Candida, and Aspergillus. Ciprofloxacin and fluconazole were used as reference standards for the activity. Among the synthesized hybrids, compounds 111–114 showed good antibacterial and antifungal activity at different concentrations. All the compounds 111–114 showed inhibition of 10–28 mm at 75 μL/mL (Scheme ) (Figure ).

24. Microwave-Assisted Synthesis of Pyranopyrimidine Derivatives 111–114 .

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Pyrimidine-containing compounds showing antimicrobial activity.

4.2. Antitubercular Activity

Mycobacterium tuberculosis is a serious threat to the lungs of infected individuals who severely cough or sneeze. This transmission is risky and fatal. To treat this condition, the FDA has already approved several drugs that are economically available, such as isoniazid, pyrazinamide, ethambutol, and rifampicin. Since these antibiotics are often inadequate, there is a great requirement to develop effective medicinal hybrids that are active against disease-causing Mycobacterium pathogens.

Sun et al. synthesized pyrimidine derivatives and tested their antitubercular activity against the Mycobacterium tuberculosis H37Rv strain. Compounds 117 and 118 exhibited the highest MICs (μg/mL) of 0.16 and 0.12, respectively. Additionally, they achieved chiral resolution of these two compounds to form R-forms 117a/118a and S-forms 117b/118b. By doing so, 117a/118a exhibited significant antitubercular activity with an MIC (μg/mL) of 0.03–0.06 against the H37Rv strain, along with low hERG toxicity. Furthermore, it was revealed that these compounds possessed good metabolic stability. The in vivo activity demonstrated that the larvae and adults of zebrafish infected with Mycobacterium marinum displayed good therapeutic action (Scheme ).

25. Synthesis of Pyrimidine Derivatives 117–118 with Chiral Resolution.

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Li and coworkers constructed novel pyrimidine hybrids and evaluated their ability to inhibit tuberculosis. The compounds were tested against Mycobacterium tuberculosis H37Ra and H37Rv strains. These compounds were also compared with the clinical drug-resistant TB. Compound 125 was identified as the lead hybrid, exhibiting remarkable potency in inhibiting strains with MIC values (μg/mL) of 0.5–1.0. Thus, compound 125 shows promise as a prime compound for treating drug-resistant TB. The SAR studies demonstrated that replacing the naphthyl group with hydrophobic substitutes, such as a phenyl ring in LPX-16j, resulted in good tolerance. LPX-16j is the potential drug candidate as an antitubercular agent. However, the presence of the core pyrimidine nucleus remains crucial for displaying significant antitubercular action in compound 125 (Scheme ).

26. Synthesis of Novel Pyrimidine Derivative 125 for Antitubercular Activity.

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Hemeda et al. produced pyrimidine-linked benzothiazole analogues and investigated their antitubercular activity against various tuberculosis strains. After careful evaluation, compounds 130, 131, 133, and 134 showed high activity against M. tuberculosis (ATCC 25177) with MIC values (μg/mL) of 0.24–0.98. Moreover, compounds 130 and 134 were very active against the resistant strain, with MIC values (μg/mL) of 0.98 and 1.95, respectively (Scheme ) (Figure ).

27. Synthesis of Pyrimidine-Linked Benzothiazole Analogues for Antitubercular Activity.

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Pyrimidine-containing compounds showing antitubercular activity.

4.3. Antidiabetic Activity

Diabetes mellitus is one of the major conditions affecting people worldwide. To combat this condition, scientists are striving to develop effective drug molecules that can significantly reduce blood glucose levels. , Various pyrimidine-containing drugs are commercially available, namely gemigliptin, linagliptin, gosogliptin, and anagliptin as listed in Table .

2. Pyrimidine-Containing Antidiabetic Drugs.

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Amin et al. synthesized thiazolidinedione-linked pyrimidine derivatives and conducted in silico studies along with biological evaluation of their antidiabetic performance. To improve hyperglycemia-related complications in diabetic people, such derivatives were constructed and studied. ADME studies revealed that compounds 141 and 142 were within the range of Lipinski’s rule of five, a well-known guideline in pharmacology. These compounds showed notable performance in the oral glucose tolerance test (OGTT) and were further subjected to an antidiabetic test in streptozotocin-induced diabetic rats for 4 weeks. It significantly reduced the blood glucose levels to 145.2 ± 1.35 and 146.6 ± 0.81, respectively. These results were even stronger than the results obtained from the standard drug pioglitazone (150.2 ± 1.06). The SAR studies revealed the importance of the thiazolidinedione moiety of compounds 141 and 142 at he position ortho to the phenoxy ring, displaying better activity than those present at the meta position. Moreover, the methoxy group at the para position in compound 141 showed better activity than compound 142 having fluorine at the same position. The isopropyl side chain linked to the sulfur atom in compounds 141–142 had greater activity than the n-propyl side chain, thus revealing the effect of the alkyl side chain on antidiabetic activity (Scheme ).

28. Synthesis of Thiazolidinedione-Linked Pyrimidine Derivatives 141–142 for Antidiabetic Activity.

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Mallidi and coworkers produced pyrimidine-tethered carbocyclic nucleoside analogues and performed in silico antidiabetic evaluations. After thorough investigation, compounds 151 and 154 showed noteworthy results against α-glucosidase with IC50 values (nmol) of 43.292 and 48.638, respectively. The E-isomers of both compounds were selectively promising because of their outstanding results (Scheme ).

29. Synthesis of Pyrimidine-Tethered Carbocyclic Nucleoside Analogues 151 and 154 for Antidiabetic Activity.

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Toan and colleagues synthesized novel pyrimidine–coumarin hybrids and studied their effectiveness toward antidiabetic properties by testing them against two well-known enzymes, viz. α-glucosidase and α-amylase, which hydrolyze glycoside linkages. Acarbose was used as the standard drug for the experiment. Compound 158 was effective against α-amylase with an IC50 value (μM) 102.32 ± 1.15, whereas compound 159 displayed an IC50 value of 115.82 ± 1.12. The reason for this slight decrease in inhibition is the change in the chloro substituent from the 3rd position to the 4th position. Compound 160 was most effective against α-glucosidase, with an IC50 value (μM) of 52.16 ± 1.12. Overall, compounds 161, 158, and 160 showed good activity with IC50 values (μM) of 82.6 ± 1.15, 96.64 ± 1.15, and 98.53 ± 1.17, respectively. Therefore, it was clear from this study that the compounds were more effective in inhibiting α-glucosidase than in inhibiting α-amylase. The SAR studies highlighted the phenomenal substitution of the phenyl ring with the chloro group in compounds 158 and 159 showed incredible inhibitory activity against α-amylase, whereas bromo groups decreased the activity. The presence of the strong electron-donating methyl and methoxy groups in compounds 160 and 161 contributed significantly to inhibiting α-glucosidase activity and decreasing α-amylase activity (Scheme ) (Figure ).

30. Synthesis of Pyrimidine-Coumarin Hybrids 158–161 for Antidiabetic Activity.

30

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5.

5

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Pyrimidine-containing analogues showing antidiabetic activity.

4.4. Comparison of Biologically Active Compounds

The overall comparison of the biologically active compounds discussed is listed in Table . With this comparative description, it is easy to locate the compounds and their actions as discussed in the above section.

3. Overall Comparison of Biologically Active Compounds.

Sl. No Biological Activity Compound No. Biological Action Reference
1. Antimicrobial 99 Inhibition of Aspergillus fumigatus (antifungal agents)
2. 100
3. 101 Inhibition of S. aureus, B. subtilis, S. typhimurium, E. coli (antibacterial agents)
4. 102
5. 103
6. 104 Inhibition of S. aureus, B. subtilis (antibacterial agents)
7. 105
8. 106 Inhibition of Aspergillus fumigatus (antifungal agent)
9. 108 Inhibition of S. aureus, S. faecalis, E. coli, K. pneumoniae, S. cerevisiae (antibacterial and antifungal agents)
10. 109
11. 111 Inhibition of Bacillus, E. coli, Pseudomonas, Candida, and Aspergillus (antibacterial and antifungal agents)
12. 112
13. 113
14. 114
15. Antitubercular 117 Inhibition of M. tuberculosis H37Rv and M. marinum (antitubercular agents)
16. 117a
17. 118
18. 118a
19. 125 Inhibition of M. tuberculosis H37Ra and H37Rv (antitubercular agent)
20. 130 Inhibition of M. tuberculosis (ATCC 25177) (antitubercular agents)
21. 131
22. 133
23. 134
24. Antidiabetic 141 Improvement of hyperglycemic conditions in diabetic patients (antidiabetic agents)
25. 142
26. 151 Effective against α-glucosidase (antidiabetic agents)
27. 154
28. 158 Effective against α-amylase (antidiabetic agents)
29. 159
30. 160 Effective against α-glucosidase (antidiabetic agents)
31. 161
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5. Conclusion

The latest progress and advances in the synthetic development of pyrimidines have had a consequential impact on the rapidly growing pharmaceutical and academic sectors. The synthetic strategies discussed here involve recent modifications and improvements in the reactions and conditions that produce lead compounds. The biological impact of pyrimidine derivatives opens a wide gateway for emerging drug development research. Therefore, the wide range of implications and scope of pyrimidines are at the heart of heterocyclic chemistry, which has led to the performance of high-class research in the development of biologically active and potent molecules. Several of the compounds discussed in this review are produced in excellent yields with different reaction optimizations and modifications. Compared with the traditional methods, the use of microwave/ultrasound-promoted synthetic methods results in lead molecules in high yields with greater purity. Direct functionalization of pyrimidines was noteworthy in providing the final compounds with favorable outcomes. A few pyrimidine-containing hybrids were even better than the standard reference drug at acting against pathogens/microorganisms. Therefore, the construction of new pyrimidine-containing analogues is necessary for the development of new biologically well-performing molecules, as infections, transmission, and other ailments have put human life at risk.

Acknowledgments

G.J.M. is thankful to the Manipal Academy of Higher Education (MAHE), Manipal, for providing Dr. T.M.A. Pai Fellowship for doctoral research.

All the data were obtained from peer-reviewed articles cited in the reference list, with no additional data sets utilized.

G.J.M.: Software, Writingoriginal draft; P.S.M.: Writingreview and editing; S.L.G.: Supervision, Writingreview and editing.

This study does not involve the use of any human beings or animals.

The authors declare no competing financial interest.

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