Design, Synthesis, Molecular Docking and Biological Evaluation of New Carbazole Derivatives as Antimicrobial Agents

Abstract

AIM: Design, synthesis, molecular docking and biological evaluation of new carbazole derivatives as antimicrobial agents

Background: Around 1.2 million people die from microbial illness each year, making it the second greatest cause of mortality in the world. As a result, medicinal chemists are constantly looking for fresh or better ways to treat microbial diseases. Carbazole derivatives have demonstrated notable biological activities among a variety of nitrogen-containing heterocyclics, with their antibacterial and antifungal properties receiving the most attention.

Objectives: To perform synthesis and biological evaluation of carbazole derivatives

Methods: The present study started with a precursor named 9H-carbazole to prepare novel heterocyclic derivatives. Treatment of carbazole with bromoethane gave intermediate-1 (InM-1), also named 9-ethyl-9H-carbazole. InM-1 was transformed into 9-ethyl-9H-carbazole-3,6-dicarbaldehyde (InM-2) through treatment with phosphorous oxychloride. The reaction of InM-2 with sodium borohydride or MeOH afforded (9-ethyl-9H-carbazole-3.6-diyl)dimethanol(InM-3).4,4'-((9-ethyl-9H-carbazole-3,diyl)bis(methylene)bis(oxy)bis(4-oxobutanoic acid) (InM-4) was obtained from the reaction of InM-3 with succinic anhydride and pyridine. InM-5 (diacid) was also obtained from InM-3 with the reaction of glutaric anhydride and pyridine. InM-4 was used to synthesize the compounds 1, 2, 3, 7, 8, and 9, while InM-5 gave the compounds 4, 5, 6, 10, 11, and 12. Synthesized compounds were characterized using TLC, MASS, and NMR spectroscopy. The molecular docking of these compounds was studied for active compounds and showed lead like characteristics.

Results: A total of 15 carbazole derivatives were synthesized, with percentage yields of 72%, 75%, 68%, 71%, 75%, 74%, 76%, 80%, 71%, 76%, 80%, 71%, 70%, 70% and 72% respectively. TLC, Mass, and NMR spectroscopy were used to characterize newly synthesized compounds, as stated in the results section. All synthesized compounds were evaluated for antifungal and antimicrobial activity against B. subtilis ATCC 6633 and E. coli ATCC 35210. The gold scores of AR101 and DHFR were found to be 61.46, while the gold scores of synthesized compounds were found in the range of 31.31–55.71. The gold score of three compounds, BR2, BR8, and BR14, was found to be above 55. Synthesized compounds proved as potential antibacterial agents.

Conclusion: Compounds 8 and 11 were synthesized with the highest yield, i.e. 80%. Synthesized compounds 3, 9, and 14 at a concentration of 3.1± 0.4 showed the most potent activity against gram-negative bacteria, i.e., E. coli, while compounds 2, 6, and 8 at the same concentration were found to be most effective against gram-positive bacteria, i.e., B. subtilis. Furthermore, compounds 5, 6, and 15 showed the most potential as therapeutic antifungals.