Aryl Substituted Benzimidazolones as Potent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors

Abstract

Since the discovery of HIV as the etiological agent of AIDS, the virus has infected millions of people each year. Fortunately, with the use of HAART, viremia can be suppressed to below detectable levels in the infected individuals, which significantly improves their quality of life and prevents the onset of AIDS. However, HAART is not curative and issues relating to adherence and drug resistance may lead to the re-emergence of viremia, the development of AIDS, and ultimately death. To address a pressing need for the development of new and efficacious antiretroviral agents with activity against viruses bearing prevalent resistant mutations, we have designed two generations of benzimidazolone derivatives as HIV non-nucleoside reverse transcriptase inhibitors. The first generation benzimidazolone inhibitors were found to be potent inhibitors of wild-type HIV reverse transcriptase but were ineffective in the presence of common resistance mutations such as K103N and Y181C. A second generation benzimidazolone inhibitor (compound 42) not only showed inhibitory activity against wild-type HIV but also remained active against HIV containing the K103N, Y181C, and K103N/Y181C drug resistance mutations.

LigTMap: ligand and structure-based target identification and activity prediction for small molecular compounds

“…In the present study, the developed predictive RF model for HIV yields an average correlation of 0.81 with RMSE of 1.28 (− log M) in the nested CV assessment (see Table 5 ). Further evaluation of the RF model was performed using 10 novel compounds reported by Pribut et al [ 42 ]. According to their study, aryl substituted benzimidazolones were experimentally validated to exhibit inhibitory effects against the HIV-1 non-nucleoside reverse transcriptase, with the reported pIC50 values in the range of 4.87–7.58.…”

“… a For the benchmark set, where no new suitable data were found in literature, the entries are marked as “–.” Sources of benchmark data are: Kinase [ 46 ], Ligase [ 47 ], BRD [ 45 ], CA [ 48 ], beta-secretase [ 49 ], HIV [ 42 ], and TB [ 50 ] …”

LigTMap: Ligand and Structure-Based Target Identification and Activity Prediction for Small Molecular Compounds

“…However, poor correlation of 0.56 was obtained, which was significantly lower than the originally reported correlation of 0.76 (Qureshi et al, 2018). Figure S5 We compared the binding modes predicted by PSOVina2 in LigTMap to the previously reported binding modes (Pribut et al, 2019). The three compounds were evaluated: 42, 50, and 54.…”

“…In the present study, the developed predictive RF model for HIV yields an average correlation of 0.81 with RMSE of 1.28 (-log M) in the nested CV assessment (see Table 4). Further evaluation of the RF model was performed using 10 novel compounds reported by Pribut et al (Pribut et al, 2019). According to their study, aryl substituted benzimidazolones were experimentally validated to exhibit inhibitory effects against the HIV-1 non-nucleoside reverse transcriptase, with the reported pIC50 values in the range of 4.87-7.58.…”

Recent Highlights in Anti‐infective Medicinal Chemistry from South Africa

“…This issue was overcome through transposition of the aromatic functionality to position 7 of the benzimidaolone scaffold ( 94 ) whose activity against wild‐type HIV, was maintained against the Y181 C and the K103 N/Y181 C double mutant. In silico data suggested that this compound formed a new electrostatic interaction with Tyr188 and Trp229, thus negating the need for an interaction with Tyr181 …”