Rational Design of Potent Non-Nucleoside Inhibitors of HIV-1 Reverse Transcriptase

Chong, Pek Y.; Sebahar, Paul R.; Youngman, Michael; Garrido, Dulce; Zhang, Huichang; Stewart, Eugene L.; Nolte, R.T.; Wang, Liping; Ferris, Robert G.; Edelstein, M.; Weaver, K.; Mathis, Amanda; Peat, Andrew J.

doi:10.1021/jm301294g

Cited by 50 publications

(44 citation statements)

References 18 publications

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“…Since the first reported sulfanyltriazole as potent non‐nucleoside reverse transcriptase inhibitor (NNRTIs) with high potency and low toxicity toward human immunodeficiency virus type‐1 (HIV‐1), much attention has been drawn in the development of novel NNRTIs based on this scaffold . Isosteric replacement of the triazole ring in sulfanyltriazole with an imidazole ring gave analogs 245a ‐ b .…”

Section: Imidazoles As Antiviral Agentsmentioning

confidence: 99%

Comprehensive Review in Current Developments of Imidazole-Based Medicinal Chemistry

et al. 2013

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Imidazole ring is an important five-membered aromatic heterocycle widely present in natural products and synthetic molecules. The unique structural feature of imidazole ring with desirable electron-rich characteristic is beneficial for imidazole derivatives to readily bind with a variety of enzymes and receptors in biological systems through diverse weak interactions, thereby exhibiting broad bioactivities. The related research and developments of imidazole-based medicinal chemistry have become a rapidly developing and increasingly active topic. Particularly, numerous imidazole-based compounds as clinical drugs have been extensively used in the clinic to treat various types of diseases with high therapeutic potency, which have shown the enormous development value. This work systematically gives a comprehensive review in current developments of imidazole-based compounds in the whole range of medicinal chemistry as anticancer, antifungal, antibacterial, antitubercular, anti-inflammatory, antineuropathic, antihypertensive, antihistaminic, antiparasitic, antiobesity, antiviral, and other medicinal agents, together with their potential applications in diagnostics and pathology. It is hoped that this review will be helpful for new thoughts in the quest for rational designs of more active and less toxic imidazole-based medicinal drugs, as well as more effective diagnostic agents and pathologic probes.

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Section: Imidazoles As Antiviral Agentsmentioning

confidence: 99%

Comprehensive Review in Current Developments of Imidazole-Based Medicinal Chemistry

et al. 2013

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“…The most recent NNRTI drug rilpivirine exhibits the flexibility to wiggle and jiggle by which it retains all of the above interactions including the key hydrogen-bonding interaction with the K101 main-chain carbonyl when it binds wild-type RT or the two double mutants [23•]. A recent study shows that an NNRTI designed to have additional hydrogen bonds with RT while maintaining its flexibility has improved resilience against resistance mutations [24]. The cyanovinyl group of rilpivirine can swivel to maintain interactions with RT ( Figure 4A ); addition of the cyanovinyl group, i.e ., chemical modification from TMC120 → rilpivirine, enhanced the inhibition potency by ~3-fold.…”

Section: Non-nucleoside Rt Inhibitors (Nnrtis)mentioning

confidence: 99%

HIV-1 reverse transcriptase and antiviral drug resistance. Part 1

Das¹,

Arnold²

2013

Current Opinion in Virology

132

133

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HIV-1 reverse transcriptase (RT) contributes to the development of resistance to all anti-AIDS drugs by introducing mutations into the viral genome. At the molecular level, mutations in RT result in resistance to RT inhibitors. Eight nucleoside/nucleotide analogs (NRTIs) and five non-nucleoside inhibitors (NNRTIs) are approved HIV-1 drugs. Structures of RT have been determined in complexes with substrates and/or inhibitors, and the structures have revealed different conformational and functional states of the enzyme. Understanding the molecular mechanisms of resistance to NRTIs and NNRTIs, and their complex relationships, may help in designing new drugs that are periodically required to overcome existing as well as emerging trends of drug resistance.

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“…In peripheral blood mono nuclear cells compound 107 also potently inhibited in the picomolar range various HIV-1 clades, independently of their coreceptor use. n IAS affinity against HIV-1 mutant RTs Antiretroviral agents [78][79][80] that were able to assume the horseshoe shape [81] binding mode proved to be uniformly active against the HIV-1 WT and drug resistant mutant strain. Docking experiments in mutated RTs (K103N, L100I, Y181C and Y188L) showed that IASs did not adopt the aforementioned horseshoe binding conformation but were still able to overcome several first and second generation NNRTIs limitations [50].…”

Section: Peptide Derivativesmentioning

confidence: 99%

Arylsulfone-Based HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors

et al. 2013

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HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) represent one of the most significant classes of drugs for the treatment of AIDS/HIV infection. Over the past two decades several potent arylsulfone-based HIV-1 NNRTIs and related analogs have been developed. This review provides an essential overview of the structure-activity relationships of the arylsulfone-based HIV-1 NNRTIs. Furthermore, structural information useful for the design and development of new sulfur containing NNRTIs with enhanced antiretroviral activity against HIV-1 wild type and clinically relevant drug resistant HIV-1 mutant strains will be discussed.

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Rational Design of Potent Non-Nucleoside Inhibitors of HIV-1 Reverse Transcriptase

Cited by 50 publications

References 18 publications

Comprehensive Review in Current Developments of Imidazole-Based Medicinal Chemistry

Comprehensive Review in Current Developments of Imidazole-Based Medicinal Chemistry

HIV-1 reverse transcriptase and antiviral drug resistance. Part 1

Arylsulfone-Based HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors

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