Targeting HIV‐TB coinfection by developing novel piperidin‐4‐substituted imines: Design, synthesis, in vitro and in silico studies

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 compounds R7, R12, R17, R18, R19, R20 were found to be more potent as anti-TB agents than ethambutol (MIC 3.125 μg/ml). Compound R7 was found to be moderately active with an IC 50 of 2.1 ± 0.04 μM in multicycle infection assays, in comparison with the standard drug, zidovudine (IC 50 = 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.

e-Pharmacophore model-guided design of potential DprE1 inhibitors: synthesis, in vitro antitubercular assay and molecular modelling studies

“…This work is in continuation of our previous reported piperidone derivatives as potential anti-HIV/TB agents (Kumar et al 2019). In the present work, we have designed non-covalent DprE1 inhibitors by developing an e-Pharmacophore model by using the receptor-ligand interactions of DprE1 with 2-carboxyquinoxalines as reported in its X-ray crystal structure (Neres et al 2015).…”

“…From this study, we can conclude that the piperidine ring substituted with furylidene rings and methyl benzimidazole ring showed potent antitubercular activity. But if we compare the antitubercular activity of parent compounds without substitution at the 4th position of piperidine ring like R2, R3, R8, R9 and R11 for which the corresponding compounds are B2, B3, B8, B9 and B11, we found that the activity was same in both the cases (Kumar et al 2019). The compounds like B4, B5, B6 and B12 were twice less potent than their unsubstituted derivatives.…”

“…Several authors have reported e-Pharmacophore modelling combined with molecular docking and molecular dynamic simulations studies to design and identify potent inhibitors of several proteins (Arun et al 2020;Kumar et al 2020Kumar et al , 2021Salam et al 2009). We have used PDB ID 4P8C to develop a fourfeature e-Pharmacophore model and mapped it against our previous reported antitubercular compounds (Kumar et al 2019). We found that only one aromatic feature matched, and our compounds had very low phase screen score.…”

A Review of the Development of Multitarget Molecules against HIV-TB Coinfection Pathogens

“…In addition, 23 was more active in ex vivo assays than the hybrid 22 (Figure 18) [102]. Kumar and coworkers [105] identified piperidine as a privileged structure with properties anti-HIV and anti-MTB. Kumar et al found that 1,4-disubstituted piperidine derivatives exhibited high anti-MTB activity [106][107][108] and moderate inhibition activity against HIV-1 [109].…”

Predictors of death among TB/HIV co-infected patients on tuberculosis treatment in Sichuan, China: A retrospective cohort study

“…TB remains the leading presenting opportunistic infection among people with HIV infection, and HIV-positive individuals are 16 to 27 times more likely to contract TB than HIV-negative individuals. [ 1 ] Moreover, TB is the leading cause of death from infectious diseases globally, causing approximately 214,000 deaths among HIV-positive people globally in 2020 (up from 209,000 in 2019) according to the World Health Organization. [ 2 ] HIV strikingly increases the risk of progression to active TB and the mortality associated with TB.…”