Piperidine scaffold as the novel P2-ligands in cyclopropyl-containing HIV-1 protease inhibitors: Structure-based design, synthesis, biological evaluation and docking study

Abstract

A series of potent HIV-1 protease inhibitors, containing diverse piperidine analogues as the P2-ligands, 4-substituted phenylsulfonamides as the P2'-ligands and a hydrophobic cyclopropyl group as the P1'-ligand, were designed, synthesized and evaluated in this work. Among these twenty-four target compounds, many of them exhibited excellent activity against HIV-1 protease with half maximal inhibitory concentration (IC 50) values below 20 nM. Particularly, compound 22a containing a (R)-piperidine-3-carboxamide as the P2-ligand and a 4-methoxylphenylsulfonamide as the P2'-ligand exhibited the most effective inhibitory activity with an IC 50 value of 3.61 nM. More importantly, 22a exhibited activity with inhibition of 42% and 26% against wild-type and Darunavir (DRV)-resistant HIV-1 variants, respectively. Additionally, the molecular docking of 22a with HIV-1 protease provided insight into the ligand-binding properties, which was of great value for further study.

Versatile Therapeutic Values of N‐Containing Heterocycles Benzimidazole, Piperazine and Piperidine Hybrids

“…reported piperidine‐based hybrids and evaluated them for anti‐viral activity. Compound 117 exhibited 42 % and 26 % inhibition against wild‐type and Darunavir (DRV)‐resistant HIV‐1 variants [163] . Xuwang et al .…”

“…Compound 117 exhibited 42 % and 26 % inhibition against wild-type and Darunavir (DRV)-resistant HIV-1 variants. [163] Xuwang et al synthesized piperidine-containing striazine hybrids and evaluated their anti-HIV activities in MT-4 cells. Compound 118 displayed extremely promising activity against wild-type HIV-1 with EC 50 values in the low nano-molar range.…”

Research Progress in HIV and Mycobacterium tuberculosis Inhibitors Containing Sulfonamide Moiety

“…A total of twenty-four compounds were synthesized, and all exhibited exceptional activity with maximal inhibitory concentration (IC 50 ) values below 20 nM. In particular, the compounds with 4-methoxylphenylsulfonamide (P2′-ligand) and (R)-piperidine-3-carboxamide (P2-ligand) gave the highest MIC value (IC 50 � 3.61 nM) and efectively inhibited wild-type HIV-1 [109].…”