Novel stilbene scaffolds efficiently target nucleoid-associated protein, HU

Novel scaffolds of stilbene were identified as inhibitors of Mycobacterium tuberculosis by targeting the nucleoid-associated protein, HU, using molecular docking. Based on the proposed combinatorial libraries I to VI, structures I and III had significantly greater docking binding energy that was comparable to that of the reference ligand, protein HU, from Mycobacterium tuberculosis. Using these docking results, 18 compounds were synthesized, characterized and evaluated for in vitro antitubercular (anti-TB) efficacy in the Mycobacterium tuberculosis strain, H37Rv. The in vitro screening results indicated a significant positive correlation between the docking binding efficacy ( r 2 > 0.5) and clogp. Compounds 3f , 3d and 4f were ranked as top scoring ligands that interacted with amino acids ARG 53, ARG 55, PRO 81, PHE 79, and LYS 13, where the -NO 2 or -Cl substitution at the para position of the 3-phenyl ring was essential for interacting of the HU protein. The hydrogen bonding with ARG 55 and LYS 13 of these compounds was similar to that with the reference ligand that inhibits the HUM tb protein. Compounds 3d , 3f , and 4f were evaluated as active leads, with MIC90 values of 21.3, 23.2 and 44.1 μM, respectively. The above mentioned compounds were also evaluated for antibacterial and antifungal efficacy in a panel of selected bacteria and fungi. Compound 3d had efficacy (MIC90: 6.82 μM) in S. aureus and E. coli . Compound 3f was also efficacious in E. coli and A. Niger , with an MIC90 value of 7.42 μM for both microorganisms. The fluoro-phenyl derivatives, 3i and 4i , were efficacious in C. albicans (MIC90 values of 8.2 and 7.8 μM, respectively) and A. niger (MIC90 values of 4.1 and 3.1 μM, respectively). Our results suggest that substitutions at the para position of 3-phenyl acryl derivatives with -NO 2 and -Cl significantly affected the binding interactions with the HUMtb protein in the docking studies. Furthermore these compounds had antitubercular and antimicrobial efficacy. The substituted phenyl acrylic acid and hydrazides could be inhibitors of the HUMtb protein of Mycobacterium tuberculosis. Novel scaffolds of stilbene were identified as inhibitors of Mycobacterium tuberculosis by targeting the nucleoid-associated protein, HU, using molecular docking.