HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) nowadays represent most promising anti-AIDS drugs that specifically inhibit HIV-1 reverse transcriptase (RT). They have a unique antiviral potency, high specificity and low cytotoxicity. However, to a great extent, the efficacy of HIV-1 NNRTIs is compounded by rapid emergence of drug resistant virus strains, which calls for continuous efforts to develop novel HIV-1 NNRTIs. Diarylpyrimidine (DAPY) derivatives, one family of NNRTIs with superior activity profiles against wild-type HIV-1 and mutant strains, have attracted considerable attention over the past few years. Among the potent lead DAPY compounds, etravirine was approved by FDA in January 2008, and its analogue rilpivirine (TMC278) has advanced to phase III clinical trials. The successful development of DAPYs results from a multidisciplinary approach involving traditional medicinal chemistry, structural biology, crystallography and computational chemistry. Recently, a number of novel characteristics of DAPYs including conformational flexibility, positional adaptability, key hydrogen bonds and specifically targeting conserved residues of RT, have been identified, providing valuable avenues for further optimization and development of new DAPY analogues as promising anti-HIV drug candidates. In this review, we first present a brief historical account of the medicinal chemistry of the DAPY NNRTIs, then focus on the extensive structural modifications, SAR studies, and binding mode analysis based on crystallographic and molecular modeling. Other structural related NNRTI scaffolds will also be reviewed.
"According to the X-ray crystallographic structures of DAPY-RT complexes and the molecular modeling studies  , the binding conformation of DAPYs resembled a characteristic horseshoe or " U " shape in the NNIBP of RT, rather than the prototypical butterflylike binding shape of the first-generation NNRTIs. The DAPY analogs generally contained three pharmacophoric moieties  : substituted benzene (A) or substituted piperidine in the protein/ solvent interface interaction domain, a heterocycle moiety containing a hydrogen bond donor and/or acceptor (B) and a hydrophobic group (C) (Fig. 1). In particular, the six-membered or bicyclic heterocycle (B) located in the center of the NNIBP, not only anchors the functional groups for well engaging with the residues around NNIBP, but also serves as key hydrogen bond acceptor and donor (NH linker) to make key hydrogen bonds with the backbone of K101. "
"HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTI) are the key drugs in efficient treatment of AIDS (de Béthune, 2010; Zhan et al., 2009). Diarylpyrimidine (DAPY) derivatives are one of the most successful families of NNRTIs developed so far (Chen et al., 2011), which have been confirmed by the approval of Etravirine (2, Fig. 1) and Rilpivirine (3, Fig. 1) for clinical use (Mordant et al., 2007). "
[Show abstract][Hide abstract] ABSTRACT: A new series of 29 diarylpyrimidine analogues featuring a cyclopropylamino group between the pyrimidine scaffold and the aryl wing have been synthesized. All of the new compounds have been characterized by spectra analysis. The target molecules were evaluated for their in vitro anti-HIV activity with FDA-approved drugs as references. Some of the compounds exhibited moderate to potent activities against wild-type HIV-1. The compound 4-((4-((cyclopropylamino)(2,5-difluorophenyl)methyl)pyrimidin-2-yl)amino)benzonitrile (1e) displayed potent anti-HIV-1 activity against WT HIV-1 with an IC50 of 0.099 μM and a selectivity index of 2302. The preliminary structure-activity relationship (SAR) of this new series of compounds was also investigated.
European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 06/2014; 62. DOI:10.1016/j.ejps.2014.06.003 · 3.35 Impact Factor
"As part of our research interest on these DAPY-like NNRTIs    , encouraged by the promising results of pyrrolopyrimidine derivatives, we conducted molecular modifications by core refinements and substituents' optimization for obtaining improved anti-HIV activity and pharmacokinetic profiles (Fig. 2). According to the bioisosterism of drug design, we employed the bridgehead nitrogen heterocycle pyrazolo[1,5-a]pyrimidine as the central ring and adopted various groups of two 'wings' of the molecule in order to explore the steric, electrical and hydrophobic effects of the nucleus and substituents, while keeping the overall molecular conformation of DAPYs which is required for the anti-RT potency. "
[Show abstract][Hide abstract] ABSTRACT: In our continuous efforts to identify novel potent HIV-1 NNRTIs, a novel class of 5,7-disubstituted pyrazolo[ 1,5-a] pyrimidine derivatives were rationally designed, synthesized and evaluated for their anti-HIV activities in MT4 cell cultures. Biological results showed that most of the tested compounds displayed excellent activity against wild-type HIV-1 with a wide range of EC50 values from 5.98 to 0.07 mu M. Among the active compounds, 5a was found to be the most promising analogue with an EC50 of 0.07 mu M against wild-type HIV-1 and very high selectivity index (SI, 3999). Compound 5a was more effective than the reference drugs nevirapine (by 2-fold) and delavirdine (by 2-fold). In order to further confirm their binding target, an HIV-1 RT inhibitory assay was also performed. Furthermore, SAR analysis among the newly synthesized compounds was discussed and the binding mode of the active compound 5a was rationalized by molecular modeling studies.
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