ABSTRACT
Based on our previous results and literature precedence, a series of 2-anilinopyridinyl-benzothiazole Schiff bases were rationally designed by performing molecular modeling experiments on some selected molecules. The binding energies of the docked molecules were better than the E7010, and the Schiff base with trimethoxy group on benzothiazole moiety, 4y was the best. This was followed by the synthesis of a series of the designed molecules by a convenient synthetic route and evaluation of their anticancer potential. Most of the compounds have shown significant growth inhibition against the tested cell lines and the compound 4y exhibited good antiproliferative activity with a GI50 value of 3.8µM specifically against the cell line DU145. In agreement with the docking results, 4y exerted cytotoxicity by the disruption of the microtubule dynamics by inhibiting tubulin polymerization via effective binding into colchicine domain, comparable to E7010. Detailed binding modes of 4y with colchicine binding site of tubulin were studied by molecular docking. Furthermore, 4y induced apoptosis as evidenced by biological studies like mitochondrial membrane potential, caspase-3, and Annexin V-FITC assays.
Subject(s)
Antimitotic Agents/chemical synthesis , Benzothiazoles/chemistry , Drug Design , Schiff Bases/chemical synthesis , Tubulin Modulators/chemical synthesis , Antimitotic Agents/chemistry , Antimitotic Agents/toxicity , Benzothiazoles/chemical synthesis , Benzothiazoles/toxicity , Binding Sites , Binding, Competitive , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Humans , Molecular Docking Simulation , Protein Structure, Tertiary , Schiff Bases/chemistry , Schiff Bases/toxicity , Structure-Activity Relationship , Tubulin/chemistry , Tubulin/metabolism , Tubulin Modulators/chemistry , Tubulin Modulators/toxicityABSTRACT
A series of 5-nitrofuran-triazole congeners were designed and synthesized by carrying out suitable structural modifications of the previously reported counterparts and were evaluated for their antimicrobial potential against both Gram-positive and Gram-negative bacterial strains. The compounds exhibited promising inhibition towards different Gram-positive pathogenic strains, while mild inhibitory effects were observed towards Gram-negative bacterial strains. Some of the compounds 9f, 9g, 9l and 9m were most active among the series, exhibiting a MIC value of 1.9 µg mL(-1) against different bacterial strains. The bactericidal activity was found to be in coherence with the bacterial growth inhibition data. The compounds were tested against fourteen different fungal strains and were found to possess excellent antifungal activities. Interestingly, all the compounds were equipotent to miconazole against one or more of the tested fungal strains and showed good activity against the other counterparts. A similar trend was observed in the case of their minimum fungicidal concentration values. Moreover, compound 9f exhibited two fold superior antifungal activity (MIC = 3.9 µg mL(-1)) than the standard miconazole (MIC = 7.8 µg mL(-1)) against C. albicans and C. parapsilosis. These compounds also effectively inhibited biofilm formation and compound 9f exhibited excellent anti-biofilm activity demonstrating a biofilm inhibitory concentration (BIC) as low as 0.8 µg mL(-1). A brief mechanistic study carried out on the most effective conjugate 9f indicated that it inhibits the ergosterol biosynthesis, thereby exhibiting antifungal effects. Molecular modelling studies carried out to study the binding modes of 9f correlates well with the antifungal activity and supported by ergosterol biosynthesis inhibition assay data. Most of these compounds exhibited ten times lower cytotoxicity toward the normal cells compared to the antimicrobial activity.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Antifungal Agents/chemical synthesis , Antifungal Agents/pharmacology , Nitrofurans/pharmacology , Triazoles/pharmacology , Anti-Bacterial Agents/chemistry , Antifungal Agents/chemistry , Candida/drug effects , Cell Line , Dose-Response Relationship, Drug , Ergosterol/antagonists & inhibitors , Ergosterol/biosynthesis , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Humans , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Nitrofurans/chemistry , Structure-Activity Relationship , Triazoles/chemistryABSTRACT
A series of 2-anilinopyridine dimers have been synthesized and evaluated for their anticancer potential. Most of the compounds have showed significant growth inhibition of the cell lines tested and compound 4d was most effective amongst the series displaying a GI50 of 0.99 µM specifically against the prostate cancer cell line (DU145). Studies to understand the mechanism of action of 4d indicates that it disrupts microtubule dynamics by inhibiting tubulin polymerization thereby arresting the cell cycle in G2/M phase. Competitive colchicine binding assay suggests that 4d binds into colchicine binding site of the tubulin. Further from some detailed biological studies like mitochondrial membrane potential, caspase-3 assay, DNA fragmentation analysis and Annexin V-FITC assay it is evident that 4d induces apoptosis.Molecular modeling studies provide an insight into the binding modes of 4d with colchicine binding site of tubulin and the data obtained correlates with the antiproliferative activity.
