Skip to main content
NCBI home page
ACS Medicinal Chemistry Letters logoLink to ACS Medicinal Chemistry Letters
. 2024 Dec 23;16(1):116–125. doi: 10.1021/acsmedchemlett.4c00491

N-Arylsulfonylated C-Homoaporphines as a New Class of Antiplatelet and Antimicrobial Agents

Bharti Rajesh Kumar Shyamlal †, Amol T Mahajan ‡, Vikash Kumar †, Aarohi Gupta †,#, Rishabh Shrivastava Ronin §, Manas Mathur §, Janmejaya Sen ‡, Sandeep Chaudhary †,‡,*
PMCID: PMC11726367  PMID: 39811136

Abstract

graphic file with name ml4c00491_0011.jpg

A series of novel N-arylsulfonylated C-homoaporphine alkaloids were synthesized under microwave irradiation and evaluated for their in vitro antiplatelet and antimicrobial activities. Among the series, compounds 12a, 12c, 12e, 12f, 12h, 12j, 12k, 12m, and 12o demonstrated highly potent (∼3-fold) platelet aggregation inhibitory activity than acetylsalicylic acid (IC50 = 21.34 μg/mL). Several N-arylsulfonylated C-homoaporphines also exhibited promising antimicrobial activity against various strains, including Macrophoma phaseolina, Trichoderma reesei, and Aspergillus niger, with minimum inhibitory concentrations (MIC) of 12.5, 6.25, and 12.5 μg/mL, respectively, comparable to Ketoconazole [MIC = 12.5 μg/mL (MP and AN strain); 6.25 μg/mL (TR strain)]. 12h showed potent antibacterial activity (IC50 = 6.25 μg/mL against Escherichia coli and Bacillus subtilis) compared to Ampicillin (IC50 = 12.5 μg/mL). After thorough structure–activity relationship (SAR) and in silico studies, C-homoaporphines were identified as a novel class of antiplatelet and antimicrobial agents.

Keywords: Alkaloids, C-Homoaporphines, Antiplatelet, Antimicrobial, Antibacterial, Molecular Docking

Aporphine 1 and C-homoaporphine 2 are tetracyclic alkaloids derived from the 1-phenethylisoquinoline structure. C-Homoaporphine 2 is homologous to aporphine 1, featuring an additional carbon atom in ring C (Figure 1). Naturally occurring homoaporphines, such as (+)-kreysigine, (−)-multifloramine, (−)-floramultine, (+)-bechuanine, and methylmerenderine iodide, are typically N-methylated on the isoquinoline ring and exhibit a penta-oxygenated biaryl moiety.1,2 In addition to the C atom in ring C, these also include the carbonyl groups, oxygen, and nitrogen atoms, forming structures like 8-oxohomoaporphine, oxahomoaporphine, and Dragabine (azahomoaporphine).3,4 So far, only two biological activities—acetylcholinesterase/butyrylcholinesterase inhibition and smooth muscle relaxation—have been reported for C-homoaporphines.1,2 As our research group is actively dedicated to synthesizing bioactive scaffolds, we recently reported the antioxidant and antiplatelet activities in aporphine skeletons.5 Modifying bioactive scaffolds, particularly aporphine alkaloids, aims to enhance pharmacological properties such as efficacy, selectivity, and safety. Although extensive research has focused on aporphine derivatives, homoaporphines remain less explored despite their potential for neuroprotective, antipsychotic, and anti-inflammatory effects. Our ongoing work suggests that introducing a sulfonamide moiety into C-Homoaporphines could yield promising new therapeutic agents, expanding their biological activity profile.

Figure 1.

Figure 1

Open in a new tab

Structural representation of aporphine 1 and the C-homoaporphine 2 class of alkaloids.

In 1960, Bradbury et al. and Badger et al.6 first isolated and characterized homoaporphine.6 Since then, various synthetic strategies have emerged, including the use of metals such as vanadium,7,8 thallium and silver,7 iron,9 ruthenium,10 palladium11 etc. for the biaryl cyclization of phenolic or phenol ether tetrahydroisoquinoline precursors. Additionally, photostimulated intramolecular ortho-arylation has been employed to form the biaryl bonds in C-homoaporphines.12

Despite synthetic methods such as acid treatment of p-quinol acetate,13 expansion of dehydroaporphines,14 Chaudhary and Harding have also reported an efficient, intramolecular direct C–H arylation of bromo-substituted tetrahydroisoquinoline precursors in excellent yields.15 Earlier our research group reported the antioxidant and antiplatelet activities of aporphine analogues that contain sulfonamide moieties.5 Compounds containing sulfonamide groups are especially known for their antimicrobial properties [e.g., sulfamethoxazole].16,17 Also, the sulfonamide analogues 3 possess promising antiplatelet activities [e.g., tirofiban, sulfinpyrazone, etc.7,8 Moreover, Eze et al. reported the amino acids analogues of benzene sulfonamides which showed promising antifungal activities against C. albicans (MIC = 6.63 mg/mL) and A. niger (MIC = 6.28 mg/mL).18 Based on the literature, like aporphines,15 we have designed, synthesized, and tested C-homoaporphine analogues for their antiplatelet and antimicrobial activity (Figure 2).

Figure 2.

Figure 2

Open in a new tab

Designing of C-homoaporphine-sulfonamide.

A literature survey indicated no reports of C-homoaporphines exhibiting antiplatelet and antimicrobial activities. We hypothesized that combining these moieties could produce promising antiplatelet and antimicrobial properties. Thus, we designed novel C-homoaporphine analogues 12a–o, derived from prototype 4, featuring modifications at the C-1/C-2 positions of ring A and sulfonamide functionality at the N6 position of ring B.5,19−21 We report their synthesis and structure–activity relationship (SAR) studies on their arachidonic acid (AA)-induced platelet aggregation inhibition, using acetylsalicylic acid as a reference, along with their antifungal and antibacterial activities compared with Ketoconazole and Ampicillin, respectively. This is the first report of novel C-homoaporphine analogues 12a–o as a new class of antiplatelet and antimicrobial agents.

We synthesized a new series of C-homoaporphine analogues 12a–o, featuring modifications at the C1/C2 positions of ring A and N-Boc at the N6 position of ring B, using reported procedures (Scheme 1; Figure 3).15 Substituted phenethylamine derivatives 7a–c were prepared via a nitroaldol reaction of aldehydes 5a–c with nitromethane, yielding nitrostyrenes 6a–c. After LAH reduction of 6a–c, we get crude primary amine 7a–c, which were further treated with 3-(2-bromo-4,5-dimethoxyphenyl) propanoic acid 8 using EDC.HCl coupling reagent, furnished amides 9a–c (84–89% yield).22 These amides underwent Bischler–Napieralski cyclization, followed by a NaBH4 reduction and Boc protection furnished N-Boc-protected bromo precursors 10a–c (90–94% yield).23

Scheme 1. Synthesis of Designed Hybrid Prototype i.e., N-Arylsulfonylated Substituted C-Homoaporphines 12a–o.

Scheme 1

Open in a new tab

Reagents and conditions: a) CH3NO2, Acetic Acid, Ammonium Acetate, Sonicator, 60–70 °C, 7–8 h; b) LAH Reduction, DCM, rt, overnight; c) EDC.HCl, HOBt, DIPEA, N2, DMF, 24 h; d) PCl5, Dry DCM, rt, 20 h; e) NaBH4, Dry MeOH, Dry DCM, f) Boc anhydride, DIPEA, DMAP, DCM, rt, 18 h; g) Pd(OAc)2, ligand PCy3HBF4, pivalic acid, K2CO3, microwave 140 °C, 15 min; h) Anhyd. ZnBr2, Dry DCM, rt, 45 min; (i) Substituted benzene sulfonyl chloride, DIPEA, DMAP, Dry DCM, rt, 3 h.

Figure 3.

Figure 3

Open in a new tab

Library of N-arylsulfonylated substituted C-homoaporphines 12a–o.

Consequently, N-Boc-protected C-homoaporphine analogues 11a–c (35–36% yield) were synthesized via microwave-assisted Pd-catalyzed direct arylation.15 Of 10a–c was produced in the presence of palladium acetate, tricyclohexylphosphine tetrafluoroborate, potassium carbonate, and pivalic acid in DMSO as solvent at 130 °C for 15 min (Scheme 1). The synthesized compounds were characterized by 1H NMR, 13C NMR, FT-IR, and high-resolution ESI-MS spectroscopic data. The NMR data of 11a–c revealed a mixture of rotamers (See SI). These analogues served as precursors for the synthesis of novel C-homoaporphine-N-6-sulfonamide hybrids 12a–o, which was achieved through dry ZnBr2/DCM-mediated N-Boc deprotection and N-sulfonylation with aryl sulfonyl chlorides in up to 95% yield (Scheme 1; Figures 3, 4).24,25

Figure 4.

Figure 4

Open in a new tab

Structural representation of the aporphine and C-homoaporphine class of alkaloids.

In Vitro Antiplatelet Activity

We recently reported the antiplatelet activities in aporphine skeleton.5 All the prepared N-arylsulfonylated C-homoaporphines 12a–o having alkoxy (OCH3 and OCH2C6H5) functional groups at C1/C2 of ring A along with substituted aryl sulfonyl (SO2Ph, SO2C6H4-4-tBu, SO2C6H4-3-CH3, SO2C6H4-4-NO2 and SO2C6H4-3-CF3) functionality at the N6 position of ring B were evaluated for their in vitro AA-induced antiplatelet aggregation inhibitory activity taking acetylsalicylic acid as the standard reference drug using the reported procedure.19 (Table 1).

Table 1. In Vitro Antiplatelet Activity of N-Arylsulfonylated Substituted C-Homoaporphines 12a–o.

graphic file with name ml4c00491_0008.jpg

Entry No. Compound No. Antiplatelet activity IC50(μg/mL)a,b
1. 12a 15.00 ± 0.22
2. 12b 36.66 ± 1.01
3. 12c 12.66 ± 0.12
4. 12d 30.00 ± 0.85
5. 12e 9.60 ± 0.08
6. 12f 12.66 ± 0.14
7. 12g 35.00 ± 0.97
8. 12h 12.67 ± 0.14
9. 12i 32.66 ± 0.94
10. 12j 8.00 ± 0.06
11. 12k 14.66 ± 0.19
12. 12l 35.00 ± 0.96
13. 12m 10.50 ± 0.08
14. 12n 30.00 ± 0.85
15. 12o 7.00 ± 0.06
16. Acetylsalicylic acid 21.34 ± 1.09
Open in a new tab
a

The results are articulated as a mean ± standard deviation (n = 3).

b

For details, see ref (19).

Table 1 summarizes the bioevaluation of compounds 12a–e, which feature the insertion of OCH3 substitutions at the C1 and C2 positions of ring A and various N-6 sulfonyl substitutions in ring B (SO2Ph, SO2C6H4-4-tBu, SO2C6H4-3-CH3, SO2C6H4-4-NO2, and SO2C6H4-3-CF3). Among these, compound 12a exhibited the most potent platelet aggregation inhibitory activity (IC50 = 15.00 ± 0.22 μg/mL), outperforming acetylsalicylic acid (IC50 = 21.34 ± 1.09 μg/mL). Compounds with electron-donating (EDG) or electron-withdrawing (EWG) groups at the para-position 12b (IC50 = 36.66 ± 1.01 μg/mL) and 12d (IC50 = 30.00 ± 0.85 μg/mL) showed reduced potency compared to acetylsalicylic acid. In contrast, compounds with EDG at the meta-position 12c (IC50 = 12.66 ± 0.12 μg/mL) or EWG at the meta-position 12e (IC50 = 9.60 ± 0.08 μg/mL) demonstrated greater potency, surpassing both acetylsalicylic acid and 12a. A similar trend was noted for compounds 12f–j, where 12f (IC50 = 12.66 ± 0.14 μg/mL) showed increased activity compared with acetylsalicylic acid. However, 12g (IC50 = 35.00 ± 0.97 μg/mL) and 12i (IC50 = 32.66 ± 0.94 μg/mL) with substitutions at the para-position exhibited lower potency. Conversely, 12h (IC50 = 12.67 ± 0.14 μg/mL) and 12j (IC50 = 8.00 ± 0.06 μg/mL) with meta-substitutions on the aryl sulfonyl segment displayed significant activity. The same pattern was observed in compounds 12k–o, with 12k (IC50 = 14.66 ± 0.19 μg/mL) showing enhanced antiplatelet activity. Compounds 12l (IC50 = 35.00 ± 0.96 μg/mL) and 12n (IC50 = 30.00 ± 0.85 μg/mL) with para-position substitutions exhibited lower potency, while 12m (IC50 = 10.50 ± 0.08 μg/mL) and 12o (IC50 = 7.00 ± 0.06 μg/mL) with meta-position substitutions demonstrated >2-fold and 3-fold more potency compared to acetylsalicylic acid. The structure–activity relationship (SAR) analysis indicated that all meta-substituted N-arylsulfonylated C-homoaporphine derivatives were active, while para-substituted ones were found less activity profile. Compounds 12a, 12c, 12e, 12f, 12h, 12j, 12k, 12m, and 12o were identified as potent antiplatelet agents, with 12e, 12j, and 12o being the most potent, which is anticipated due to the meta-CF3 group in their arylsulfonyl moiety. The benzyloxy substitutions at the C1/C2 positions of ring A also slightly enhanced the antiplatelet activity.

Our previous study observed that an aporphine skeleton with a sulfonamide substituent at the N6 position exhibits significantly less activity than antiplatelet agents. In contrast, homoaporphine analogues with a sulfonamide substituent at the N6 position demonstrate excellent potency. Thus, the homologation of the aporphine core yielded a novel homoaporphine moiety, which shows potent in vitro antiplatelet activity.

In Vitro Antifungal Activity

N-arylsulfonylated substituted C-homoaporphines 12a–o were also assessed for their in vitro antifungal activity against Macrophoma phaseolina (MP), Trichoderma reesei (TR), Aspergillus niger (AN) strains using ketoconazole as a reference standard drug.26 The details of the activities are shown in Table 2.

Table 2. In Vitro Antifungal Activity of N-Arylsulfonylated Substituted C-Homoaporphines 12a–oa.

graphic file with name ml4c00491_0009.jpg

Entry No. Compound No. b[MP] MIC (μg/mL) c[TR] MIC (μg/mL) d[AN] MIC (μg/mL)
1. 12a NA NA 25
2. 12b 6.25 NA 100
3. 12c NA 12.5 12.5
4. 12d 12.5 NA 50
5. 12e 12.5 NA 25
6. 12f NA NA 6.25
7. 12g NA NA 12.5
8. 12h 25 12.5 12.5
9. 12i 12.5 NA 25
10. 12j 12.5 25 25
11. 12k NA NA NA
12. 12l 25 50 6.25
13. 12m 50 25 NA
14. 12n 12.5 6.25 50
15. 12o NA 6.25 NA
16. eKetoconazole 12.5 6.25 12.5
Open in a new tab
a

MIC of all compounds was measured at 100 μg/mL.

b

MP, Macrophoma phaseolina.

c

TR, Trichoderma reesei.

d

AN, Aspergillus niger.

e

KET: Ketoconazole; NA = Compounds which were found not active.

The standard drug ketoconazole exhibited MIC values of 12.5 μg/mL, 6.25 μg/mL, and 12.5 μg/mL against Macrophoma phaseolina [MP], Trichoderma reesei [TR], and Aspergillus niger [AN] strains, respectively. Compounds 12a–e were initially evaluated, with 12a showing inactivity against [MP] and [TR] and lower activity against the [AN] strain. In contrast, compound 12b (MIC = 6.25 μg/mL), featuring an EDG at the para-position of the sulfonyl group, exhibited double the activity of ketoconazole against [MP] strain but was inactive against [TR] strain and less active against [AN] strain. Compound 12c (MIC = 12.5 μg/mL) was equipotent to ketoconazole against [AN] and showed activity against the [TR] strain but was inactive against the [MP] strain. Compounds 12d (MIC = 12.5 μg/mL) and 12e (MIC = 12.5 μg/mL), with EWG at meta and para positions, respectively, exhibited activity similar to that of ketoconazole against the [MP] strain but were inactive against the [TR] strain and less active against the [AN] strain. The vanillin-based C-homoaporphine analogues 12f–j showed similar patterns. Compound 12f (MIC = 6.25 μg/mL) was inactive against [MP] and [TR] strains but displayed 2-fold potency against [AN] strain. Compound 12g (MIC = 12.5 μg/mL) was equipotent to ketoconazole against the [AN] strain, as was 12h (MIC = 12.5 μg/mL), which contained a CH3 group at the meta-position. Compounds 12i–j with EWG substitutions showed profiles similar to those of 12d–e, being equipotent to the standard against the [MP] strain but inactive against the other strains. Further analysis of compounds 12k–o, which had a -Bn group at the C-2 position and various substitutions, revealed that 12k was inactive in all strains. However, 12l (MIC = 6.25 μg/mL) with a tBu group at the para-position showed double the activity of ketoconazole against the [AN] strain. Compound 12m, with an EDG at the meta-position, did not improve activity against any strains. In contrast, 12n with EWG at the meta-position exhibited equipotent activity to ketoconazole against the [MP] strain (MIC = 12.5 μg/mL) and greater activity against the [TR] strain (MIC = 6.25 μg/mL). Similarly, 12o displayed equal potency to ketoconazole against the [TR] strain but was inactive against the [MP] and [AN] strains. Overall, only compound 12b showed 2-fold more antifungal activity against the [MP] strain, while compounds 12d–e, 12i–j, and 12n were equipotent against the [MP] strain. Compounds 12n and 12o were 2-fold more potent than ketoconazole against the [TR] strain. Additionally, compounds 12c and 12g–h were equipotent against the [AN] strain, and compounds 12f and 12l demonstrated double the antifungal activity compared with ketoconazole against the [AN] strain.

In Vitro Antibacterial Activity

N-arylsulfonylated C-homoaporphines 12a–o were also assessed for in vitro antibacterial activity against two different Gram-negative bacterial strains Escherichia coli [EC] (MTCC 443), and Gram-positive Bacillus subtilis [BS] (MTCC 10619) strains, utilizing the agar diffusion assay.27−29 The antibiotic ampicillin was used as a positive control. The antibacterial screening of 12a–o and a positive control was performed at a fixed concentration of 100 μg/mL. Many of the synthesized compounds exhibited antibacterial activity against Gram-positive and Gram-negative bacterial strains. The minimum inhibitory concentration (MIC) values for all the N-arylsulfonylated C-homoaporphines 12a–o and the positive control drugs were also determined against bacteria using the serial dilution method.30,31 The details of the study are listed in Table 3.

Table 3. In vitro Antibacterial Activity of N-Arylsulfonylated Substituted C-Homoaporphines 12a-oa.

graphic file with name ml4c00491_0010.jpg

Entry No. Compound No. bE. coli(EC) Values (μg/mL) (Gram-negative) cBacillus subtilis(BS) Values (μg/mL) (Gram-positive)
1. 12a 12.5 50
2. 12b 3.125 12.5
3. 12c 6.25 25
4. 12d NA NA
5. 12e 25 100
6. 12f NA NA
7. 12g 6.25 NA
8. 12h 3.125 3.125
9. 12i 50 12.5
10. 12j 6.25 25
11. 12k NA 12.5
12. 12l NA 25
13. 12m 50 25
14. 12n 12.5 NA
15. 12o 6.25 6.25
16. dAmpicillin 12.5 25
Open in a new tab
a

MIC of all compounds was measured at 100 μg/mL.

b

Gram-positive bacteria: BS, Bacillus subtilis.

c

Gram-negative bacteria: EC, Escherichia coli.

d

AMP: Ampicillin; NA = Compounds which were found not active.

The standard ampicillin had MIC values of 12.5 μg/mL against the Escherichia coli [EC] strain and 25 μg/mL against the Bacillus subtilis [BS] strain. Compounds 12a–e, featuring OCH3 substitutions at C1 and C2 of ring A and various sulfonyl groups at N-6 in ring B, were tested against these strains. Compound 12a (IC50 = 12.5 μg/mL) was as effective as ampicillin against the [EC] strain but inactive against the [BS] strain. Compounds with EDG at the para-position 12b showed strong activity against both strains (IC50 = 3.125 μg/mL for [EC] and 12.5 μg/mL for [BS]). In contrast, those with EDG at the meta-position 12c had moderate activity (IC50 = 6.25 μg/mL for the [EC] strain and 25 μg/mL for the [BS] strain. Compound 12d, with an EWG at para-position, was inactive, while 12e with EWG at meta-position displayed moderate activity against [EC] (IC50 = 25 μg/mL) strain but was less effective against [BS] strain. The vanillin-based 12f–j showed similar profiles. Compound 12f was inactive, while 12g with EDG at the para-position exhibited enhanced activity against [EC] strain (IC50 = 6.25 μg/mL) but was inactive against [BS] strain. Compound 12h was found to be the most potent (IC50 = 3.125 μg/mL) against both strains. Compounds 12i (IC50 = 50 and 12.5 μg/mL) and 12j (IC50 = 6.25 and 25 μg/mL) showed moderate activity against [EC] and [BS] strains, respectively. Further SAR studies on compounds 12k–o, with a benzyl group at C-2, indicated that the presence of a benzyl group was not beneficial. Compounds 12k and 12l were inactive against the [EC] strain, while 12l was equipotent against the [BS] strain. Compound 12m (IC50 = 50 and 25 μg/mL) with EDG at meta-position, had reduced activity against both the strains. Compound 12n having an EWG at the meta-position was equipotent against the [EC] strain but inactive against the [BS] strain. Compound 12o (IC50 = 6.25 μg/mL) having EWG at the meta-position demonstrated strong activity against both the strains. In summary, compounds 12b, 12h, and 12o showed potent antibacterial effects, while compounds 12d and 12f were inactive. Compounds 12g, 12k, 12l, and 12n were ineffective against one of the strains, while compounds 12a, 12c, 12e, 12g, 12i, 12j, and 12m displayed moderate activity against both the strains.

Molecular Docking

Molecular docking studies were performed using AutoDock Vina.32 To assess the binding affinities of the most active compounds 12o, 12n, and 12h against acetylsalicylic acid, ketoconazole, and ampicillin as reference standards. (Figure 5). The crystal structures of the antiplatelet target (PDB ID: 2OYE),33 antifungal target (PDB ID: 3LD6)34 and antibacterial target (PDB ID: 1JIJ),35 respectively, were used for the in silico studies. For the visualization of docking, Biovia Discovery Studio software was used.

Figure 5.

Figure 5

Open in a new tab

Molecular docking studies of 12o, 12n, and 12h in comparison with standard references i.e., acetal salicylic acid, ketoconazole, and ampicillin, respectively: (a) Interaction of compound 12o with antiplatelet target 2OYE; (b) Interaction of standard Aspirin with antiplatelet target 2OYE; (c) Interaction of compound 12n with antifungal target 3LD6; (d) Interaction of standard Ketoconazole with antifungal target 3LD6; e) Interaction of compound 12h with antibacterial target 1JIJ; f) Interaction of standard Ampicillin with antibacterial target 1JIJ.

The most active compound, 12o, was docked against the antiplatelet target 2OYE, showing a binding energy score of −8.6 kcal/mol. It formed a Pi-sigma interaction with LEU123 and a Pi-alkyl interaction with LEU93, VAL116, and VAL119. Compound 12o demonstrated superior binding affinity compared to acetylsalicylic acid, which had a binding energy score of −6.2 kcal/mol. Acetylsalicylic acid exhibited conventional hydrogen bonding with SER530 and Pi-alkyl interactions with LEU352 and ALA527 (Figure 5b). For the antifungal target 3LD6, the most active compound 12n was compared with the reference ketoconazole. Compound 12n displayed a binding energy score of −10.7 kcal/mol, while ketoconazole had a binding energy score of −10 kcal/mol. The methoxy group of 12n formed a hydrogen bond with PRO441 and a π-donor hydrogen bond with TYR145. It also exhibited π-sulfur interactions with MET380 and CYS449 as well as π–π stacking with PHE234. Additionally, 12n showed π-alkyl interactions with LEU159, ILE377, and ALA311. Ketoconazole demonstrated π-sulfur interactions with MET100 and π–π stacking with TYR131 and TRP239, along with π-alkyl interaction with TYR145 (Figure 5d).

Compound 12h was docked against the antibacterial target 1JIJ, having a binding energy score of −7.9 kcal/mol, compared to −8.0 kcal/mol for standard ampicillin. The methoxy group of 12h exhibited π-alkyl interactions with VAL224 and LEU52, while the benzyloxy group showed an π-alkyl interaction with PRO53. Additionally, a π–π T-shaped interaction was noted between HIS50 and the adjacent benzene ring, along with a π-anion and carbon–hydrogen bond interaction with ASP195. Ampicillin formed three conventional hydrogen bonds with TYR170, LYS84, and ASP195, and its benzene ring exhibited π–π sulfur, π-alkyl, and T-shaped interactions, along with two carbon–hydrogen interactions with ALA39.

In Silico ADME Study

Using SwissADME software,36 we assessed the physicochemical properties and drug-likeness of the synthesized compounds 12a–o. The Lipinski rule, a key guideline in drug development, predicts the pharmacological behavior of candidates and is essential for evaluating their activity before in vivo testing. To qualify as a potential drug, a biologically active molecule must meet specific criteria: molar mass <500, hydrogen bond acceptors <10, hydrogen bond donors <5, and MlogP < 5. Compounds 12a–o adhered to these criteria, exhibiting high oral bioavailability, favorable pharmacokinetic profiles, and desirable drug-like characteristics. Predictive analysis indicated that these compounds do not cross the blood-brain barrier (BBB). Their bioavailability scores were comparable to those of standard reference drugs such as acetylsalicylic acid, ketoconazole, and ampicillin, underscoring their promising bioavailability and pharmacokinetics. Furthermore, compounds 12a–o complied with Lipinski’s hydrogen bond rules, reinforcing their drug-likeness, as shown in Table 4. A boiled egg diagram from SwissADME illustrates the compound’s BBB permeation, absorption, and efflux by P-glycoprotein (Figure 6).

Table 4. Drug-Likeness Properties of Compounds 12o.

Sr. No. Compound MW(g/mol) MLogP < 5 Hydrogen bond acceptors Hydrogen bond donors Lipinski violations Bioavailability score
1. 12a 495.59 2.55 7 0 0 0.55
2. 12b 551.69 3.32 7 0 1 0.55
3. 12c 509.61 2.75 7 0 1 0.55
4. 12d 540.58 1.69 9 0 1 0.55
5. 12e 563.59 3.04 10 0 1 0.55
6. 12f 571.68 3.49 7 0 1 0.55
7. 12g 627.79 4.21 7 0 1 0.55
8. 12h 585.71 3.67 7 0 1 0.55
9. 12i 616.68 2.64 9 0 1 0.55
10. 12j 639.68 3.94 10 0 1 0.55
11. 12k 571.68 3.49 7 0 1 0.55
12. 12l 627.79 4.21 7 0 1 0.55
13. 12m 585.71 3.67 7 0 1 0.55
14. 12n 616.68 2.64 9 0 1 0.55
15. 12o 639.68 3.94 10 0 1 0.55
16. Acetylsalicylic acid 180.16 1.51 4 1 0 0.85
17. Ketoconazole 531.43 2.47 5 0 1 0.55
18. Ampicillin 349.40 0.75 5 3 0 0.55
Open in a new tab

Figure 6.

Figure 6

Open in a new tab

Boiled-egg diagram obtained from SwissADME software.

Figure 6 illustrates the ADME profiles of compounds 12a–o alongside the standard compound’s acetylsalicylic acid, ketoconazole, and ampicillin, numbered 1 to 18 (corresponding to Sr. No. 1–18). Acetylsalicylic acid and ketoconazole fall within the yellow region, indicating that they are predicted to passively permeate the blood-brain barrier. In contrast, ampicillin, located in the white region, is expected to be passively absorbed in the gastrointestinal tract. Molecules represented by blue dots are anticipated to be expelled from the central nervous system by P-glycoprotein, while those marked with red dots are predicted to not interact with the central nervous system.

Conclusion

For the first time, microwave-assisted synthesis of novel N-sulfonylated substituted C-homoaporphine analogues 12a–o have been prepared and assessed for their in vitro antiplatelet as well as antimicrobial activities. Among the series, compounds 12a, 12c, 12e, 12f, 12h, 12j, 12k, 12m, and 12o exhibited highly potent (∼3-fold) platelet aggregation inhibitory activity as compared to standard reference acetylsalicylic acid (IC50 = 21.34 μg/mL). Similarly, several N-arylsulfonylated C-homoaporphines have also shown promising antifungal activities against different strains, i.e., MP: Macrophoma phaseolina; TR: Trichoderma reesei; AN: Aspergillus niger, whereas ketoconazole is used as a standard reference with MIC values of 12.5, 6.25, and 12.5 μg/mL, respectively. Similarly, compounds 12b, 12h, and 12o displayed potent antibacterial activity. Compound 12h was found to be the most active compound with (IC50 = 6.25 μg/mL) against both Gram-negative [ES] strain as well as Gram-positive [BS] strain. The molecular docking analysis was also performed for all of the synthesized molecules against the 2OYE, 3LD6, and 1JIJ targets. Our findings qualify the studied molecules as prospective antiplatelet and antimicrobial agents with distinct tunable structures that pave the way for further advanced applications. To the best of our knowledge, N-arylsulfonylated substituted C-homoaporphines have been identified as a new class of antiplatelet and antimicrobial agents.

Acknowledgments

S.C. acknowledges the Science and Engineering Research Board (SERB) [Grant No. CRG/2019/005102], New Delhi for providing research grant. B.R.K.S. is thankful to UGC, New Delhi, for providing financial assistance in the form of a Senior Research Fellowship (SRF). A.T.M. and J.S. are grateful to the Department of Pharmaceuticals (DoP), Ministry of Chemicals and Fertilizers, and Government of India for providing a Junior Research Fellowship (JRF) and Senior Research Fellowship, respectively. Materials Research Centre (MRC), MNIT, Jaipur, and Central Instrumentation Facility (CIF), NIPER-Raebareli are gratefully acknowledged for providing analytical facilities. The NIPER-Raebareli manuscript communication number is NIPER-R/Communication/580.

Glossary

Abbreviations

AA

Arachidonic acid

COX

cyclooxygenase

IC

Inhibitory concentration

LEU

leucine

VAL

valine

SER

serine

ALA

alanine

PRO

proline

TYR

tyrosine

CYS

cysteine

PHE

phenylalanine

MET

methionine

ILE

isoleucine

TRP

tryptophan

HIS

histidine

ASP

aspartic acid

LYS

lysine

ARG

arginine

GLY

glycine

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.4c00491.

  • Lay summary (PDF)

  • General experimental and characterization data of 6a–c; 8; 7a–c; 9a–c; 10a–c; 11a–c and 12a–o; 1H-NMR and 13C-NMR spectral data of compounds 6a–c; 8; 7a–c; 9a–c; 10a–c; 11a–c and 12a–o and 12a–o; biological methods (in vitro antiplatelet activity, in vitro antifungal activity and in vitro antibacterial activity) and molecular docking analysis (PDF)

Author Contributions

B.R.K.S and A.T.M. contributed equally. S.C. conceived the idea, designed the hypothesis, and managed the overall manuscript preparation. B.R.K.S, A.T.M., V.K., A.G., and J.S. were responsible for the synthesis and characterization of all the synthesized compounds and in the preparation of the Supporting Information. B.R.K.S, A.T.M., and J.S. prepared the draft preparation and writing of the manuscript. R.S.R. and M.M. are responsible for biological experiments and data analysis. S.C. carried out the writing and corrections of the whole manuscript. All authors have read and approved the final version of the manuscript.

This study was funded by the Science and Engineering Research Board (SERB) [Grant No. CRG/2019/005102], New Delhi.

The authors declare no competing financial interest.

Special Issue

Published as part of ACS Medicinal Chemistry Lettersspecial issue “Celebrating the 25th Anniversary of the Chemical Research Society of India”.

Supplementary Material

ml4c00491_si_001.pdf (236.3KB, pdf)
ml4c00491_si_002.pdf (4.2MB, pdf)

References

  1. Tojo E. The Homoaporphine Alkaloids. J. Nat. Prod 1989, 52 (5), 909–921. 10.1021/np50065a001. [DOI] [Google Scholar]
  2. Tojo E.; Zarga M. H. A.; Sabri S. S.; Freyer A. J.; Shamma M. The Homoaporphine Alkaloids of Androcymbium Palaestinum. J. Nat. Prod 1989, 52 (5), 1055–1059. 10.1021/np50065a023. [DOI] [Google Scholar]
  3. Paz W. H. P.; de Oliveira R. N.; Heerdt G.; Angolini C. F. F.; S. de Medeiros L.; Silva V. R.; Santos L. S.; Soares M. B. P.; Bezerra D. P.; Morgon N. H.; Almeida J. R. G. S.; da Silva F. M. A.; Costa E. V.; Koolen H. H. F. Structure-Based Molecular Networking for the Target Discovery of Oxahomoaporphine and 8-Oxohomoaporphine Alkaloids from Duguetia Surinamensis. J. Nat. Prod 2019, 82 (8), 2220–2228. 10.1021/acs.jnatprod.9b00287. [DOI] [PubMed] [Google Scholar]
  4. Cassels B. K.; Cavé A.; Davoust D.; Hocquemiller R.; Rasamizafy S.; Tadić D. Azahomoaporphines: A New Heterocyclic Skeleton from Annonaceae. J. Chem. Soc. Chem. Commun. 1986, 19, 1481–1483. 10.1039/C39860001481. [DOI] [Google Scholar]
  5. Shyamlal B. R. K.; Mathur M.; Yadav D. K.; Chaudhary S. Microwave-Assisted Modified Synthesis of C8-Analogues of Naturally Occurring Methylxanthines: Synthesis, Biological Evaluation and Their Practical Applications. Fitoterapia 2020, 143, 104533 10.1016/j.fitote.2020.104533. [DOI] [PubMed] [Google Scholar]
  6. Badger G. M.; Bradbury R. B. 85. The Alkaloids of Kreysigia Multiflora Reichb. Part I. Isolation. J. Chem. Soc. Chem. (Resumed) 1960, 445–447. 10.1039/jr9600000445. [DOI] [Google Scholar]
  7. Gilmartin P. H.; Kozlowski M. C. Vanadium-Catalyzed Oxidative Intramolecular Coupling of Tethered Phenols: Formation of Phenol-Dienone Products. Org. Lett. 2020, 22 (8), 2914–2919. 10.1021/acs.orglett.0c00577. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Kupchan S. M.; Dhingra O. P.; Kim C.-K.; Kameswaran V. Novel Nonphenol Oxidative Coupling of Phenethylisoquinolines. J. Org. Chem. 1976, 41 (25), 4047–4049. 10.1021/jo00887a034. [DOI] [Google Scholar]
  9. Herbert R. B.; Kattah A. E.; Murtagh A. J.; Sheldrake P. W. Use of Iron (III) Chloride in the Efficient Preparation of the Alkaloid Kreysigine by Oxidative Coupling. Tetrahedron Lett. 1995, 36 (31), 5649–5650. 10.1016/0040-4039(95)01037-I. [DOI] [Google Scholar]
  10. Landais Y.; Rambault D.; Robin J. P. Ruthenium (IV) Tetrakis (Trifluoroacetate), a New Oxidizing Agent. III. An Efficient Access to the Aporphine and Homoaporphine Skeletons and Their Structural Studies. Tetrahedron Lett. 1987, 28 (5), 543–546. 10.1016/S0040-4039(00)95777-0. [DOI] [Google Scholar]
  11. Cuny G. D. Intramolecular Ortho-Arylation of Phenols Utilized in the Synthesis of the Aporphine Alkaloids (±)-Lirinidine and (±)-Nuciferine. Tetrahedron Lett. 2003, 44 (44), 8149–8152. 10.1016/j.tetlet.2003.09.026. [DOI] [Google Scholar]
  12. Barolo S. M.; Teng X.; Cuny G. D.; Rossi R. A. Syntheses of Aporphine and Homoaporphine Alkaloids by Intramolecular Ortho-Arylation of Phenols with Aryl Halides via SRN1 Reactions in Liquid Ammonia. J. Org. Chem. 2006, 71 (22), 8493–8499. 10.1021/jo061478+. [DOI] [PubMed] [Google Scholar]
  13. Hoshino o.; Toshioka t.; Ohyama k.; Umezawa b. Studies on Tetrahydroisoquinolines. VII. Synthesis of Homoaporphine via a p-(14) Quinol Acetate; Total Synthesis of (±)-Kreysigine. Chem. Pharm. Bull. (Tokyo) 1974, 22 (6), 1307–1312. 10.1248/cpb.22.1307. [DOI] [Google Scholar]
  14. Castro J. L.; Castedo L.; Riguera R. Ring C Homologation of Aporphines. A New Synthesis of Homoaporphines. J. Org. Chem. 1987, 52 (16), 3579–3584. 10.1021/jo00392a015. [DOI] [Google Scholar]
  15. Chaudhary S.; Harding W. W. Synthesis of C-Homoaporphines via Microwave-Assisted Direct Arylation. Tetrahedron 2011, 67 (3), 569–575. 10.1016/j.tet.2010.11.059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Chohan Z. H.; Rauf A.; Naseer M. M.; Somra M. A.; Supuran C. T. Antibacterial, Antifungal and Cytotoxic Properties of Some Sulfonamide-Derived Chromones. J. Enzyme Inhib Med. Chem. 2006, 21 (2), 173–177. 10.1080/14756360500533059. [DOI] [PubMed] [Google Scholar]
  17. Chohan Z. H. Metal-Based Antibacterial and Antifungal Sulfonamides: Synthesis, Characterization, and Biological Properties. Transit. Met. Chem. 2009, 34, 153–161. 10.1007/s11243-008-9171-y. [DOI] [Google Scholar]
  18. Eze F. U.; Okoro U. C.; Ugwu D. I.; Okafor S. N. Biological Activity Evaluation of Some New Benzenesulphonamide Derivatives. Front Chem. 2019, 7, 634. 10.3389/fchem.2019.00634. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Shyamlal B. R. K.; Yadav L.; Tiwari M. K.; Mathur M.; Prikhodko J. I.; Mashevskaya I. V.; Yadav D. K.; Chaudhary S. Synthesis, Bioevaluation, Structure-Activity Relationship and Docking Studies of Natural Product Inspired (Z)-3-Benzylideneisobenzofuran-1 (3H)-Ones as Highly Potent Antioxidants and Antiplatelet Agents. Sci. Rep 2020, 10 (1), 2307. 10.1038/s41598-020-59218-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Sharma V.; Jaiswal P. K.; Kumar S.; Mathur M.; Swami A. K.; Yadav D. K.; Chaudhary S. Discovery of Aporphine Analogues as Potential Antiplatelet and Antioxidant Agents: Design, Synthesis, Structure-Activity Relationships, Biological Evaluations, and in Silico Molecular Docking Studies. ChemMedChem. 2018, 13 (17), 1817–1832. 10.1002/cmdc.201800318. [DOI] [PubMed] [Google Scholar]
  21. Sharma V.; Jaiswal P. K.; Kumar K.; Saran M.; Mathur M.; Swami A. K.; Chaudhary S. An Efficient Synthesis and Biological Evaluation of Novel Analogues of Natural Product Cephalandole A: A New Class of Antimicrobial and Antiplatelet Agents. Fitoterapia 2018, 129, 13–19. 10.1016/j.fitote.2018.06.003. [DOI] [PubMed] [Google Scholar]
  22. Albericio F. Developments in Peptide and Amide Synthesis. Curr. Opin Chem. Biol. 2004, 8 (3), 211–221. 10.1016/j.cbpa.2004.03.002. [DOI] [PubMed] [Google Scholar]
  23. Sotomayor N.; Domínguez E.; Lete E. Bischler– Napieralski Cyclization– N/C-Alkylation Sequences for the Construction of Isoquinoline Alkaloids. Synthesis of Protoberberines and Benzo [c] Phenanthridines via C-2 ‘-Functionalized 3-Arylisoquinolines1. J. Org. Chem. 1996, 61 (12), 4062–4072. 10.1021/jo960007s. [DOI] [PubMed] [Google Scholar]
  24. Chaudhary S.; Ponnala S.; LeGendre O.; Gonzales J. A.; Navarro H. A.; Harding W. W. New Aporphinoid 5-HT2A and A1A Antagonists via Structural Manipulations of Nantenine. Bioorg. Med. Chem. 2011, 19 (19), 5861–5868. 10.1016/j.bmc.2011.08.019. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Dunetz J. R.; Magano J.; Weisenburger G. A. Large-Scale Applications of Amide Coupling Reagents for the Synthesis of Pharmaceuticals. Org. Process Res. Dev 2016, 20 (2), 140–177. 10.1021/op500305s. [DOI] [Google Scholar]
  26. Igwe C. N.; Okoro U. C. Synthesis, Characterization, and Evaluation for Antibacterial and Antifungal Activities of n-Heteroaryl Substituted Benzene Sulphonamides. Org. Chem. Int. 2014, 2014, 1. 10.1155/2014/419518. [DOI] [Google Scholar]
  27. Alam S. Synthesis, Antibacterial and Antifungal Activity of Some Derivatives of 2-Phenyl-Chromen-4-One. J. Chem. Sci. 2004, 116 (6), 325–331. 10.1007/BF02711433. [DOI] [Google Scholar]
  28. Muralidhar Reddy P.; Ho Y. P.; Shanker K.; Rohini R.; Ravinder V. Physicochemical and Biological Characterization of Novel Macrocycles Derived from O-Phthalaldehyde. Eur. J. Med. Chem. 2009, 44 (6), 2621–2625. 10.1016/j.ejmech.2008.09.035. [DOI] [PubMed] [Google Scholar]
  29. Shahidi Bonjar S. A.; Aghighi S.; Karimi Nik A. Antibacterial, and Antifungal Survey in Plants Used in Indigenous Herbal-Medicine of South East Regions of Iran. J. Biol. Sci. 2004, 4 (3), 405–412. 10.3923/jbs.2004.405.412. [DOI] [Google Scholar]
  30. Cruickshank R.Medical Microbiology: The Practice of Medical Microbiology; Churchill Livingstone, 1975; Vol. II. [Google Scholar]
  31. Uzun O.; Arikan S.; Kocagoz S.; Sancak B.; Unal S. Susceptibility Testing of Voriconazole, Fluconazole, Itraconazole, and amphotericin B against Yeast Isolates in a Turkish University Hospital and Effect of Time of Reading. Diagn Microbiol Infect Dis 2000, 38, 101–107. 10.1016/S0732-8893(00)00177-2. [DOI] [PubMed] [Google Scholar]
  32. Trott O.; Olson A. J. AutoDock Vina: Improving the Speed and Accuracy of Docking with a New Scoring Function, Efficient Optimization, and Multithreading. J. Comput. Chem. 2010, 31 (2), 455–461. 10.1002/jcc.21334. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Harman C. A.; Turman M. V.; Kozak K. R.; Marnett L. J.; Smith W. L.; Garavito R. M. Structural Basis of Enantioselective Inhibition of Cyclooxygenase-1 by S-α-Substituted Indomethacin Ethanolamides*. J. Biol. Chem. 2007, 282 (38), 28096–28105. 10.1074/jbc.M701335200. [DOI] [PubMed] [Google Scholar]
  34. Strushkevich N.; Usanov S. A.; Park H.-W. Structural Basis of Human CYP51 Inhibition by Antifungal Azoles. J. Mol. Biol. 2010, 397 (4), 1067–1078. 10.1016/j.jmb.2010.01.075. [DOI] [PubMed] [Google Scholar]
  35. Qiu X.; Janson C. A.; Smith W. W.; Green S. M.; McDevitt P.; Johanson K.; Carter P.; Hibbs M.; Lewis C.; Chalker A.; Fosberry A.; Lalonde J.; Berge J.; Brown P.; Houge-Frydrych C. S. V; Jarvest R. L. Crystal Structure of Staphylococcus Aureus Tyrosyl-TRNA Synthetase in Complex with a Class of Potent and Specific Inhibitors. Protein Sci. 2001, 10, 2008–2016. 10.1110/ps.18001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Daina A.; Michielin O.; Zoete V. SwissADME: A Free Web Tool to Evaluate Pharmacokinetics, Drug-Likeness and Medicinal Chemistry Friendliness of Small Molecules. Sci. Rep 2017, 7, 1–13. 10.1038/srep42717. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ml4c00491_si_001.pdf (236.3KB, pdf)
ml4c00491_si_002.pdf (4.2MB, pdf)

Articles from ACS Medicinal Chemistry Letters are provided here courtesy of American Chemical Society

RESOURCES