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Design, synthesis, and preclinical evaluations of novel 4-substituted 1,5-diarylanilines as potent HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI) drug candidates.

ABSTRACT: Twenty-one new 4-substituted diarylaniline compounds (DAANs) (series 13, 14, and 15) were designed, synthesized, and evaluated against wild-type and drug resistant HIV-1 viral strains. As a result, approximately a dozen new DAANs showed high potency with low nano- to subnanomolar EC(50) values ranging from 0.2 to 10 nM. The three most promising compounds 14e, 14h, and 15h exhibited high potency against wild-type and drug-resistant viral strains with EC(50) values at the subnanomolar level (0.29-0.87 nM) and were comparable to or more potent than the new NNRTI drug riplivirine (2) in the same assays. Druglike physicochemical property assessments revealed that the most active DAANs (EC(50) < 10 nM) have better aqueous solubility (>1-90 ?g/mL at pH 7.4 and pH 2) and metabolic stability in vitro than 2, as well as desirable log P values (<5) and polar surface areas (PSA) (<140 Å(2)). These promising results warrant further development of this novel compound class as potential potent anti-AIDS clinical trial candidates.

SUBMITTER: Sun LQ

PROVIDER: S-EPMC3462592 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Design, synthesis, and preclinical evaluations of novel 4-substituted 1,5-diarylanilines as potent HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI) drug candidates.

Sun Lian-Qi LQ Zhu Lei L Qian Keduo K Qin Bingjie B Huang Li L Chen Chin Ho CH Lee Kuo-Hsiung KH Xie Lan L

Journal of medicinal chemistry 20120810 16

Twenty-one new 4-substituted diarylaniline compounds (DAANs) (series 13, 14, and 15) were designed, synthesized, and evaluated against wild-type and drug resistant HIV-1 viral strains. As a result, approximately a dozen new DAANs showed high potency with low nano- to subnanomolar EC(50) values ranging from 0.2 to 10 nM. The three most promising compounds 14e, 14h, and 15h exhibited high potency against wild-type and drug-resistant viral strains with EC(50) values at the subnanomolar level (0.29- ...[more]

PMID: 22856541

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Project description:Despite achieving considerable success in reducing the number of fatalities due to acquired immunodeficiency syndrome, emergence of resistance against the reverse transcriptase (RT) inhibitor drugs remains one of the biggest challenges of the human immunodeficiency virus antiretroviral therapy (ART). Non-nucleoside reverse transcriptase inhibitors (NNRTIs) form a large class of drugs and a crucial component of ART. In NNRTIs, even a single resistance mutation is known to make the drugs completely ineffective. Additionally, several inhibitor-bound RTs with single resistance mutations do not exhibit any significant variations in their three-dimensional structures compared with the inhibitor-bound RT but completely nullify their inhibitory functions. This makes understanding the structural mechanism of these resistance mutations crucial for drug development. Here, we study several single resistance mutations in the allosteric inhibitor (nevirapine)-bound RT to analyze the mechanism of small structural changes leading to these large functional effects. In this study, we have shown that in absence of significant conformational variations in the inhibitor-bound wild-type RT and RT with single resistance mutations, the protein contact network analysis of their static structures, along with molecular dynamics simulations, can be a useful approach to understand the functional effect of small local conformational variations. The simple network analysis exposes the localized contact changes that lead to global rearrangement in the communication pattern within RT. Furthermore, these conformational changes have implications on the overall dynamics of RT. Using various measures, we show that a single resistance mutation can change the network structure and dynamics of RT to behave more like unbound RT, even in the presence of the inhibitor. This combined coarse-grained contact network and molecular dynamics approach promises to be a useful tool to analyze structure-function studies of proteins that show large functional changes with negligible variations in their overall conformation.

Dataset Information

Design, synthesis, and preclinical evaluations of novel 4-substituted 1,5-diarylanilines as potent HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI) drug candidates.

Publications

Design, synthesis, and preclinical evaluations of novel 4-substituted 1,5-diarylanilines as potent HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI) drug candidates.

Similar Datasets

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