Exploiting the tolerant region I of the non-nucleoside reverse transcriptase inhibitor (NNRTI) binding pocket. Part 2: Discovery of diarylpyrimidine derivatives as potent HIV-1 NNRTIs with high Fsp3 values and favorable drug-like properties

Jiang, Xiangyi; Huang, Boshi; Olotu, Fisayo A.; Li, Jing; Kang, Dongwei; Wang, Zhao; Clercq, Erik De; Soliman, Mahmoud E. S.; Pannecouque, Christophe; Liu, Xinyong; Zhan, Peng

doi:10.1016/j.ejmech.2020.113051

Cited by 19 publications

(13 citation statements)

References 44 publications

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“…Extensive research conducted in our laboratory and by others in the last decade have led to the discovery of several diarylpyrimidine-type HIV-1 NNRTIs targeting the tolerant region I and/or the tolerant region II of NNIBP with remarkably improved anti-resistance profiles, as well as desirable drug-like properties (Figure ). ,,− These results have confirmed the feasibility of rational molecular design of new “multi-site binding” NNRTIs, targeting the dual tolerant regions of NNIBP.…”

Section: Introductionmentioning

confidence: 67%

Structure-Based Design and Discovery of Pyridyl-Bearing Fused Bicyclic HIV-1 Inhibitors: Synthesis, Biological Characterization, and Molecular Modeling Studies

et al. 2021

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Two series of new pyridyl-bearing fused bicyclic analogues designed to target the dual-tolerant regions of the non-nucleoside reverse transcriptase inhibitor (NNRTI)-binding pocket were synthesized and evaluated for their anti-HIV activities. Several compounds, such as 6, 14, 15, 21, 30, and 33, were found to be potent inhibitors against the wild-type (WT) HIV-1 strain or multiple NNRTI-resistant strains at low nanomolar levels. Detailed structure–activity relationships were obtained by utilizing the variation of moieties within the corresponding pharmacophores. In vitro metabolic stability profiles and some drug-like properties of selected compounds were assessed, furnishing the preliminary structure–metabolic stability relationships. Furthermore, molecular modeling studies elucidated the binding modes of compounds 6, 15, 21, and 30 in the binding pocket of WT, E138K, K103N, or Y181C HIV-1 RTs. These promising compounds can be used as lead compounds and warrant further structural optimization to yield more active HIV-1 inhibitors.

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Section: Introductionmentioning

confidence: 67%

Structure-Based Design and Discovery of Pyridyl-Bearing Fused Bicyclic HIV-1 Inhibitors: Synthesis, Biological Characterization, and Molecular Modeling Studies

et al. 2021

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“…The DAPY class typically suffers from poor aqueous solubility, which can contribute to low bioavailability and drug-like properties. Hence, the development of novel DAPY-like inhibitors with high potency against the WT virus and resistant viral strains, as well as improved aqueous solubility, is highly desirable. − Numerous publications ,− and reviews ,, on DAPY NNRTIs have been recently published. In several cases, another (hetero)cycle was attached to the pyrimidine central core of molecules to form fused bicyclic NNRTIs in order to explore the entrance channel of the NNRTI binding pocket. ,,, In our current work, we decided to substitute the pyrimidine core of ETV and RPV (Figure ) with modified bicyclic cores in order to introduce an additional polar moiety, which should result in increased aqueous solubility.…”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of Novel HIV-1 NNRTIs with Bicyclic Cores and with Improved Physicochemical Properties

et al. 2023

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Non-nucleoside reverse transcriptase inhibitors (NNRTIs) represent cornerstones of current regimens for treatment of human immunodeficiency virus type 1 (HIV-1) infections. However, NNRTIs usually suffer from low aqueous solubility and the emergence of resistant viral strains. In the present work, novel bicyclic NNRTIs derived from etravirine (ETV) and rilpivirine (RPV), bearing modified purine, tetrahydropteridine, and pyrimidodiazepine cores, were designed and prepared. Compounds 2, 4, and 6 carrying the acrylonitrile moiety displayed single-digit nanomolar activities against the wild-type (WT) virus (EC 50 = 2.5, 2.7, and 3.0 nM, respectively), where the low nanomolar activity was retained against HXB2 (EC 50 = 2.2−2.8 nM) and the K103N and Y181C mutated strains (fold change, 1.2− 6.7×). Most importantly, compound 2 exhibited significantly improved phosphate-buffered saline solubility (10.4 μM) compared to ETV and RPV (≪1 μM). Additionally, the binding modes of compounds 2, 4, and 6 to the reverse transcriptase were studied by Xray crystallography.

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“…154,155 Guided by this design assumption, different saturated polar groups were introduced to enrich the SARs around the solventexposed region, leading to the identification of compound 67, which displayed improved drug resistance profiles against several single mutant strains and favorable water solubility (Table 7). 156…”

Section: Introducing Hydrophilic Groups Into Thementioning

confidence: 99%

Contemporary Medicinal Chemistry Strategies for the Discovery and Development of Novel HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors

et al. 2022

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Currently, HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) are a major component of the highly active anti-retroviral therapy (HAART) regimen. However, the occurrence of drug-resistant strains and adverse reactions after long-term usage have inevitably compromised the clinical application of NNRTIs. Therefore, the development of novel inhibitors with distinct anti-resistance profiles and better pharmacological properties is still an enormous challenge. Herein, we summarize state-of-the-art medicinal chemistry strategies for the discovery of potent NNRTIs, such as structure-based design strategies, contemporary computer-aided drug design, covalent-binding strategies, and the application of multi-target-directed ligands. The strategies described here will facilitate the identification of promising HIV-1 NNRTIs.

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Exploiting the tolerant region I of the non-nucleoside reverse transcriptase inhibitor (NNRTI) binding pocket. Part 2: Discovery of diarylpyrimidine derivatives as potent HIV-1 NNRTIs with high Fsp3 values and favorable drug-like properties

Cited by 19 publications

References 44 publications

Structure-Based Design and Discovery of Pyridyl-Bearing Fused Bicyclic HIV-1 Inhibitors: Synthesis, Biological Characterization, and Molecular Modeling Studies

Structure-Based Design and Discovery of Pyridyl-Bearing Fused Bicyclic HIV-1 Inhibitors: Synthesis, Biological Characterization, and Molecular Modeling Studies

Design and Synthesis of Novel HIV-1 NNRTIs with Bicyclic Cores and with Improved Physicochemical Properties

Contemporary Medicinal Chemistry Strategies for the Discovery and Development of Novel HIV-1 Non-nucleoside Reverse Transcriptase Inhibitors

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