Targeting HIV‐TB coinfection by developing novel piperidin‐4‐substituted imines: Design, synthesis, in vitro and in silico studies. Issue 6 (8th May 2019)

• Record Type: Journal Article
• Authors: Kumar, Avinash; Revathi, Rajappan; Sriram, Dharmarajan; Curreli, Francesca; Debnath, Asim K.; Pai, K. Sreedhara; Kini, Suvarna G.
• Is Part Of: Archiv der Pharmazie. Volume 352:Issue 6(2019)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-05-08
• Subjects: enoyl‐acyl carrier protein reductase -- HIV -- Mycobacterium tuberculosis -- piperidine -- reverse‐transcriptase; Pharmaceutical chemistry -- Periodicals; Pharmacology -- Periodicals; 615.19
• DOI: 10.1002/ardp.201800358
• Languages: English
• ISSNs: 0365-6233

Abstract

Abstract: Tuberculosis is the "Achilles heel" of the human immunodeficiency (HIV) ministration. HIV‐positive people are 16–27 times more prone to contract tuberculosis. But the adverse interaction between antiretroviral drugs and antitubercular drugs has made it necessary to look for a single drug regimen for HIV‐TB coinfection. Piperidine derivatives have been reported as anti‐HIV and anti‐TB agents. This inspired us to design, synthesize, and characterize a series of 3, 5‐bis(furan‐2‐ylmethylidene)‐piperidin‐4‐substituted imines (R1‐R25 ) and these were further screened for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv and anti‐HIV activity. Molecular docking studies showed energetically favorable binding interactions with both EACP reductase (1ZID.pdb) and reverse‐transcriptase (1REV.pdb) targets. The compoundsR7, R12, R17, R18, R19, R20 were found to be more potent as anti‐TB agents than ethambutol (MIC 3.125 μg/ml). CompoundR7 was found to be moderately active with an IC50 of 2.1 ± 0.04 μM in multicycle infection assays, in comparison with the standard drug, zidovudine (IC50 = 5.7 ± 0.04 nM), used as anti‐HIV drug. The cytotoxicity assay was done on Vero, MT‐2, and TZM‐bl cells to assess the safety of these compounds and they were found to be safe. From the above results, R7 seems to be a promising lead for anti‐HIV and anti‐TB activity. Abstract : In search for a single‐drug regimen for human immunodeficiency‐tuberculosis (HIV‐TB) coinfection, new 3, 5‐bis(furan‐2‐ylmethylidene)piperidin‐4‐substituted imines (R1‐R25 ) were designed, synthesized and screened for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv and anti‐HIV activity. Molecular docking studies showed favorable binding interactions with enoyl‐ACP‐reductase and reverse‐transcriptase.R7 seems to be a promising lead for anti‐HIV and anti‐TB activity.