Targeting the entrance channel of NNIBP: Discovery of diarylnicotinamide 1,4-disubstituted 1,2,3-triazoles as novel HIV-1 NNRTIs with high potency against wild-type and E138K mutant virus

Abstract

Inspired by our previous efforts on the modifications of diarylpyrimidines as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTI) and reported crystallography study, novel diarylnicotinamide derivatives were designed with a "triazole tail" occupying the entrance channel in the NNRTI binding pocket of the reverse transcriptase to afford additional interactions. The newly designed compounds were then synthesized and evaluated for their anti-HIV activities in MT-4 cells. All the compounds showed excellent to good activity against wild-type HIV-1 strain with EC of 0.02-1.77 μM. Evaluations of selected compounds against more drug-resistant strains showed these compounds had advantage of inhibiting E138K mutant virus which is a key drug-resistant mutant to the new generation of NNRTIs. Among this series, propionitrile (3b2, EC = 0.020 μM, EC = 0.015 μM, CC = 40.15 μM), pyrrolidin-1-ylmethanone (3b8, EC = 0.020 μM, EC = 0.014 μM, CC = 58.09 μM) and morpholinomethanone (3b9, EC = 0.020 μM, EC = 0.027 μM, CC = 180.90 μM) derivatives are the three most promising compounds which are equally potent to the marketed drug Etravirine against E138K mutant strain but with much lower cytotoxicity. Furthermore, detailed SAR, inhibitory activity against RT and docking study of the representative compounds are also discussed.

1,2,3-Triazole-containing hybrids as leads in medicinal chemistry: A recent overview

“…130 Moreover, 99 interacted strongly with recombinant HIV-1 CA and exhibited antiviral potential in the early and late stages of HIV-1 replication. New 1,4-disubstituted 1,2,3-triazole-bearing diarylnicotinamides were examined for anti-HIV potentials against wild-type (WT, IIIB and ROD) and multiple mutant strains by Tian et al 131 Three of the most potent lead derivatives identified were 100 (EC 50(IIIB) = 0.020 µM, EC 50(E138K) = 0.015 µM, CC 50 = 40.15 µM), 101 (EC 50(IIIB) = 0.020 µM, EC 50(E138K) = 0.014 µM, CC 50 = 58.09 µM), and 102 (EC 50(IIIB) = 0.020 µM, EC 50(E138K) = 0.027 µM, CC 50 = 180.90 µM; Fig. 12), which showed equal promising potency against the E138K mutant strain.…”

CuAAC-ensembled 1,2,3-triazole-linked isosteres as pharmacophores in drug discovery: review

“…The results indicate that the presence of nitro and cyano group at the 3 rd position on benzyl ring 63 increases the activity of the compound against HIV-1, as shown in the molecule. 103 Phenylalanine derivatives that were also synthesized via click chemistry exhibit excellent anti-HIV activity. Compound 64 has very high activity against HIV-1 NL4-3 strain with much lesser toxicity because of the presence of b-substituted naphthalene, which is directly bound to triazole.…”

New N‐phenylacetamide‐linked 1,2,3‐triazole‐tethered coumarin conjugates: Synthesis, bioevaluation, and molecular docking study

“…great attention due to their extensive biological properties such as antioxidant, [5] antifungal, [6,7] antitubercular, [8] antibacterial, [9] anticancer, [10] anti-HIV, [11] antimicrobial, [12] and antimalarial activity. [13] The 1,4-disubstituted-1,2,3-triazoles were synthesized via coppercatalyzed azide-alkyne cycloaddition reaction, well known as a click chemistry reaction.…”