New 3-[(tetrazol-5-yl)methine-N-benzylamine)]-1H-indole derivatives: Synthesis, anti-HIV activity and molecular docking studies

In this study, we report a one-pot Ugi four-component synthesis of a new series of drug-like 3-[(tetrazol-5-yl)methine- N -benzylamine)]-1 H -indoles ( 10a-p ) that target the HIV attachment and reverse transcription stages. Ten compounds ( 10b-c , 10e , 10i-j and 10l-p ) exhibited potent antiviral efficacy, with IC 50 values ranging from 0.0106 μM to 19.2 μM, and were noncytotoxic (CC 50 values > 100 μM ). Specifically, 10e (IC 50 = 39 ± 5 nM), 10i (IC 50 = 10.6 ± 0.1 nM) and 10n (IC 50 = 88 ± 7.5 nM) were more active than the control drug, azidothymidine (AZT), with 10e and 10i showing 2.3- and 8.3-fold superior activity, respectively. Compounds 10i and 10o displayed activities in the early stages of viral infection in the time of addition studies, with the strongest inhibition occurring between 1 and 3 hours (coinciding with the viral attachment) and moderate inhibition from 3 to 6 hours (coinciding with the reverse transcription (RT)), suggesting a potential dual inhibitory activity against two critical viral stages. Following confirmatory assays, compounds 10i and 10o strongly inhibited HIV viral entry in the gp120 assay, while showing weak to moderate inhibition of reverse transcription in the HIV RT assay. Both compounds showed moderate to no inhibitory activity against RT mutant viruses (V241I, I257V, P272K and E297K), but maintained their activities against the wild-type virus. Molecular docking and dynamic simulations elucidated the putative binding modes and delineated critical interactions with amino acid residues, such as TRP427, GLY473, ASP368, LYS101, TY181 and TRP229. This study establishes these indole-tetrazole-based compounds as promising dual viral attachment and reverse transcriptase inhibitors, providing valuable starting points for further development. 3-[(tetrazol-5-yl)methine- N -benzylamine)]-1 H -indole derivatives were synthesised using the Ugi four-component reaction (Ugi-4CR). Compound 10i was identified as the most promising with IC 50 = 10.6 nM against the HIV-1 subtype B and acceptable cytotoxicity (CC 50 = 1967 μM and SI > 18,000). In vitro time of addition (TOA) studies revealed this compound to be a potentially strong inhibitor of the viral entry/attachment phase (1-3 hours, 100% inhibition) of the HIV lifecycle. Confirmatory assay confirmed the TOA studies, with these compounds exhibiting stronger inhibition of the viral attachment and moderate to no activity against RT mutant strains. Molecular docking studies showed potential binding modes with critical amino acid residues in gp120 and reverse transcriptase receptors. • Synthesis of a new series of 3-[(tetrazol-5-yl)methine- N -benzylamine)]-1 H -indole derivatives ( 10a-p ), using a one-pot Ugi four-component (Ugi-4CR), in moderate to excellent yields. • Ten compounds ( 10b-c , 10e , 10i-j and 10l-p ) were potent with IC 50 values in the nanomolar and low micromolar range against HIV-1 subtype B virus. • Twelve compounds also exhibited a good cytotoxicity profile with CC 50 > 100 μM. • In vitro time of addition studies on HIV-1 subtype B showed these compounds to be strong inhibitors of the viral attachment phase of the virus lifecycle, while also being moderate inhibitors of reverse transcriptase. • RT enzyme and gp120 inhibition data confirmed the time of addition studies by exhibiting strongly inhibitory activity against gp120 and moderate activity against RT enzyme. • These compounds exhibited moderate to no inhibitory activity against RT mutant strains, but maintained their activity against wild-type viruses. • In silico docking studies elucidated the putative binding modes and delineated critical interactions between the compounds and receptors, while molecular dynamics revealed stable and flexible complexes.