Recent advances in DAPYs and related analogues as HIV-1 NNRTIs.
ABSTRACT 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.
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ABSTRACT: Two simple, rapid, sensitive and economic chromatographic methods have been developed for the determination of Rilpirivine. First method depends on reverse phase high performance liquid chromatography. The mobile used consists of using mixed phosphate buffer: acetonitrile (60:40%v/v) with pH 6.8 and flow rate of 1.0ml/min in isocratic mode. The separation was carried out by UV detector at wavelength 272nm. A concentration range from 1-10 µg/ml was used for calibration curve. The percent recovery of rilpirivine was found to be 100.53%. Second method depends on high performance thin layer liquid chromatography. The mobile phase used consists of ethyl acetate: methanol: chloroform (8.0:1.0: 1.0%v/v/ v).Densiometric analysis was carried out at wavelength 254nm. The Rf value for rilpirivine was found to be 0.33. A concentration range from 5-30 µg/spot was used for calibration curve. The percent recovery of rilpirivine was found to be 100.17%. HPLC and HPTLC methods are widely employed in quality control assessment of drugs because of their sensitivity, repeatability and specificity. The proposed method was validated statically and recovery study for the determination of rilpirivine in bulk and in tablet dosage form was performed.World Journal of Pharmaceutical Research 08/2012; 1(4):1183-1196. · 5.05 Impact Factor
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ABSTRACT: Heterocyclic substances perform a very unique role in drug design and discovery. This article provides the primary objectives of the analysis within pyrimidine centered new heterocyclic elements chronologically from their finding focusing on one of the essential enzyme of HIV virus particle that is integrase upon suppressing its strand transfer function. The class of compounds reviewed here includes bicyclic pyrimidines, dihydroxypyrimidines, pyrimidine-2,4-dinones, N-methylpyrimidones, pyranopyrimidine, pyridine-quinoline conjugates, pyrimidine-2-carboxamides, N-3 hydroxylated pyrimidine-2,4-diones as well as their various substituted analogues. Such initiatives released an effective drug Reltagravir as a first FDA approved anti-HIV integrase inhibitor as well as several of its derivatives along with other pyrimidones is under clinical or preclinical growth. Some of the provided scaffolds indicated dual anti-HIV efficacies against HIV reverse transcriptase and integrase enzymes at both cites as 3’-processing and strand transfer, while several scaffolds exhibited potency against Reltagravir resistant HIV mutant strains determining themselves a potent class of compounds having appealing upcoming implementations. Connections of the new compounds’ molecular structure and HIV viral target has been overviewed to be able to accomplish further growth of promising anti-HIV agents in future drug discovery process.European Journal of Medicinal Chemistry 07/2014; · 3.43 Impact Factor
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ABSTRACT: Sirtuins are a class of enzymes with nicotinamide adenine dinucleotide (NAD)-dependent protein lysine deacylase function. By deacylating various substrate proteins, including histones, transcription factors, and metabolic enzymes, sirtuins regulate various biological processes, such as transcription, cell survival, DNA damage and repair, and longevity. Small molecules that can inhibit sirtuins have been developed and many of them have shown anticancer activity. Here, we summarize the major biological findings that connect sirtuins to cancer and the different types of sirtuin inhibitors developed. Interestingly, biological data suggest that sirtuins have both tumor-suppressing and tumor-promoting roles. However, most pharmacological studies with small-molecule inhibitors suggest that inhibiting sirtuins has anticancer effects. We discuss possible explanations for this discrepancy and suggest possible future directions to further establish sirtuin inhibitors as anticancer agents.Future medicinal chemistry 05/2014; 6(8):945-66. · 3.31 Impact Factor