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Synthesis, Antimicrobial Evaluation and Molecular Docking of Some Potential 2,6-disubstituted 1H-Benzimidazoles; Non-Classical Antifolates


Sunil Harer*, Manish Bhatia and Vikram Kawade  


Background: Dihydrofolate reductase is one of the important enzymes for thymidylate and purine synthesis in micro-organisms. A large number of drugs have been designed to inhibit microbial DHFR but over the period of time some drugs have developed resistance and cross reactivity towards the enzyme. Over the past few decades, benzimidazoles, triazoles and their derivatives have been grabbing the attention of the synthetic chemists for their wide gamut of antibacterial and antifungal activities targeting microbial protein DHFR.

Objective: Our goal behind present investigation is to explore benzimidazoles class of drugs as microbial DHFR inhibitors by studying ligand-receptor binding interactions, in vitro enzyme inhibition assay and confirmation of anti-microbial activity against selected pathogenic micro-organisms.

Method: A library containing thirty novel 2,6-disubstituted 1H-benzimidazoles was synthesized by one pot condensation of o-nitro aniline or 2,4-dinitro aniline with series of aldehydes or acetophenones using Na2S2O4 or SnCl2 respectively and reflux for 5-6hr. Structures of compounds have been confirmed by spectroscopic methods as 1H and 13C NMR, FT-IR and MS. In vitro DHFR inhibition study was performed by using Epoch microplate reader and IC50 of the test compounds was compared with Trimethoprim. In vitro antimicrobial activity was performed against selected clinical pathogens by agar disk diffusion method and MIC (µg/mL) was reported.

Results: Moderate to good level of DHFR inhibition was observed with IC50 values in the range of 7-23 µM. Compounds B1, B19, B22, B24 and B30 has expressed 1.1 to 1.4 folds more prominent DHFR inhibitory activity as compared to standard Trimethoprim. Remarkable antimicrobial activity was exhibited by B1, B19, B22, B24 and B30. Molecular docking study has revealed perfect binding of test ligands with key amino acids of DHFR as Phe31, Ile94, Ile5, Asp27, Gln32 and Phe36.

Conclusion: Nature of 1H-benzimidazole substituents at position 2 and 6 had influence over magnitude and type of molecular binding and variation in the biological activity. Present series of 1H-benzimidazoles could be considered promising broad-spectrum antimicrobial candidates that deserve in future for preclinical antimicrobial evaluation and development of newer antimicrobial agents targeting microbial DHFR.


1H-benzimidazoles, DHFR, molecular modeling, antimicrobial activity, agar disk diffusion, MIC, IC50.


Department of Pharmaceutical Chemistry, Sharadchandra Pawar College of Pharmacy, Faculty of Pharmaceutical Sciences, Savitribai Phule Pune University, Pune (MS), Department of Pharmaceutical Chemistry, Bharati Vidyapeeth College of Pharmacy, Faculty of Pharmaceutical Sciences, Shivaji University, Kolhapur (MS), Department of Pharmaceutical Chemistry, Bharati Vidyapeeth College of Pharmacy, Faculty of Pharmaceutical Sciences, Shivaji University, Kolhapur (MS)

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