Design, Microwave-Assisted Synthesis, Antimicrobial and Anticancer Evaluation, and In Silico Studies of Some 2-Naphthamide Derivatives as DHFR and VEGFR-2 Inhibitors.

Naphthamide is a common structural framework with diverse pharmacological activities. Ten novel 2-naphthamide derivatives have been designed, synthesized, and evaluated for their in vitro antibacterial, antifungal, and anticancer activities. The title compounds were synthesized from dimethoxybenzaldehyde derivatives through a four-step microwave-assisted synthesis process. The structures were confirmed by 1H NMR, 13C NMR, and MS spectra. Compound 8b showed good antibacterial activity against Escherichia coli, Streptococcus faecalis, Salmonella enterica, MSSA, and MRSA with MIC values of 16, 16, 16, 8, and 16 µg/mL, respectively, compared to ciprofloxacin (MIC = 8-16 µg/mL). Compounds 5b (IC50 = 3.59-8.38 µM) and 8b (IC50 = 2.97-7.12 µM) exhibited good cytotoxic activity against C26, HepG2, and MCF7 cancer cell lines as compared to paclitaxel (IC50 = 2.85-5.75 µM). Moreover, compounds 5b and 8b exhibited better anticancer activity than PTX against the C26 cell line. In particular, compound 8b showed potent in vitro VEGFR-2 inhibitory activity with the IC50 value of 0.384 µM compared with sorafenib (IC50 = 0.069 µM). Therefore, compound 8b is the most potent compound for anticancer activity as indicated by in vitro cell line inhibition, in silico ADMET, molecular docking, and in vitro VEGFR-2 inhibition studies.

Design, synthesis, bio-evaluation, and in silico studies of some N-substituted 6-(chloro/nitro)-1H-benzimidazole derivatives as antimicrobial and anticancer agents.

A new series of 6-substituted 1H-benzimidazole derivatives were synthesized by reacting various substituted aromatic aldehydes with 4-nitro-o-phenylenediamine and 4-chloro-o-phenylenediamine through condensation using sodium metabisulfite as the oxidative reagent. The N-substituted 6-(chloro/nitro)-1H-benzimidazole derivatives were prepared from the 6-substituted 1H-benzimidazole derivatives and substituted halides using potassium carbonate by conventional methods as well as by exposure to microwave irradiation. Seventy-six 1H-benzimidazole derivatives have been synthesized in moderate to excellent yields with the microwave-assisted method (40 to 99%). Compounds 1d, 2d, 3s, 4b, and 4k showed potent antibacterial activity against Escherichia coli, Streptococcus faecalis, MSSA (methicillin-susceptible strains of Staphylococcus aureus), and MRSA (methicillin-resistant strains of Staphylococcus aureus) with MIC (the minimum inhibitory concentration) ranging between 2 and 16 µg mL-1 as compared to ciprofloxacin (MIC = 8-16 µg mL-1), in particular compound 4k exhibits potent fungal activity against Candida albicans and Aspergillus niger with MIC ranging between 8 and 16 µg mL-1 compared with the standard drug fluconazole (MIC = 4-128 µg mL-1). In addition, compounds 1d, 2d, 3s, 4b, and 4k also showed the strongest anticancer activity among the synthesized compounds against five tested cell lines with IC50 (half-maximal inhibitory concentration) ranging between 1.84 and 10.28 µg mL-1, comparable to paclitaxel (IC50 = 1.38-6.13 µM). Furthermore, the five most active compounds showed a good ADMET (absorption, distribution, metabolism, excretion, and toxicity) profile in comparison to ciprofloxacin, fluconazole, and paclitaxel as reference drugs. Molecular docking predicted that dihydrofolate reductase protein from Staphylococcus aureus is the most suitable target for both antimicrobial and anticancer activities, and vascular endothelial growth factor receptor 2 and histone deacetylase 6 are the most suitable targets for anticancer activity of these potent compounds.

Synthesis of a Series of Novel 2-Amino-5-substituted 1,3,4-oxadiazole and 1,3,4-thiadiazole Derivatives as Potential Anticancer, Antifungal and Antibacterial Agents.

BACKGROUND: Many compounds containing a five-membered heterocyclic ring display exceptional chemical properties and versatile biological activities. OBJECTIVE: The objective of the present study was to prepare the 5-substituted 2-amino-1,3,4- oxadiazole and 2-amino-1,3,4-thiadiazole derivatives and evaluate their potential anticancer, antibacterial and antifungal activities. METHODS: Twenty-seven derivatives were synthesized by iodine-mediated cyclization of semicarbazones or thiosemicarbazones obtained from condensation of semicarbazide or thiosemicarbazide and aldehydes. The structures were confirmed by 1H-NMR, 13C-NMR and MS spectra. The antibacterial and antifungal activities were evaluated by diffusion method and the anticancer activities were evaluated by MTT assay. RESULTS: Twenty-seven derivatives have been synthesized in moderate to good yields. A number of derivatives exhibited potential antibacterial, antifungal and anticancer activities. CONCLUSION: Compounds (1b, 1e and 1g) showed antibacterial activity against Streptococcus faecalis, MSSA and MRSA with MIC value ranging between 4 to 64 µg/mL. Compound (2g) showed antifungal activity against Candida albicans (8 µg/mL) and Aspergillus niger (64 µg/mL). Compound (1o) exhibited high cytotoxic activity against HepG2 cell line (IC50 value 8.6 µM) which is comparable to the activity of paclitaxel, and is non-toxic on LLC-PK1 normal cell line. The structure activity relationship and molecular docking study of the synthesized compounds have also been reported.

N,2,6-Trisubstituted 1H-benzimidazole derivatives as a new scaffold of antimicrobial and anticancer agents: design, synthesis, in vitro evaluation, and in silico studies.

Compounds containing benzimidazole moiety occupy privileged chemical space for discovering new bioactive substances. In continuation of our recent work, 69 benzimidazole derivatives were designed and synthesized with good to excellent yields of 46-99% using efficient synthesis protocol i.e. sodium metabisulfite catalyzed condensation of aromatic aldehydes with o-phenylenediamines to form 2-arylbenzimidazole derivatives followed by N-alkylation by conventional heating or microwave irradiation for diversification. Potent antibacterial compounds against MSSA and MRSA were discovered such as benzimidazole compounds 3k (2-(4-nitrophenyl), N-benzyl), 3l (2-(4-chlorophenyl), N-(4-chlorobenzyl)), 4c (2-(4-chlorophenyl), 6-methyl, N-benzyl), 4g (2-(4-nitrophenyl), 6-methyl, N-benzyl), and 4j (2-(4-nitrophenyl), 6-methyl, N-(4-chlorobenzyl)) with MIC of 4-16 µg mL-1. In addition, compound 4c showed good antimicrobial activities (MIC = 16 µg mL-1) against the bacteria strains Escherichia coli and Streptococcus faecalis. Moreover, compounds 3k, 3l, 4c, 4g, and 4j have been found to kill HepG2, MDA-MB-231, MCF7, RMS, and C26 cancer cells with low µM IC50 (2.39-10.95). These compounds showed comparable drug-like properties as ciprofloxacin, fluconazole, and paclitaxel in computational ADMET profiling. Finally, docking studies were used to assess potential protein targets responsible for their biological activities. Especially, we found that DHFR is a promising target both in silico and in vitro with compound 4c having IC50 of 2.35 µM.