A5103019050- HIV/AIDS drug development and treatment
- HIV Research and Treatment
- Pneumocystis jirovecii pneumonia detection and treatment
- Click Chemistry and Applications
- Chemical Synthesis and Analysis
- Biochemical and Molecular Research
- HIV/AIDS Research and Interventions
- Hepatitis C virus research
- Computational Drug Discovery Methods
- SARS-CoV-2 and COVID-19 Research
- Chemical Reaction Mechanisms
- Tuberculosis Research and Epidemiology
- DNA and Nucleic Acid Chemistry
- COVID-19 Clinical Research Studies
- Amino Acid Enzymes and Metabolism
Shandong University
2007-2025
Institute of Theoretical Physics
2007
To address drug resistance to HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), a series of novel diarylpyrimidine (DAPY) derivatives targeting "tolerant region I" and II" the NNRTIs binding pocket (NNIBP) were designed utilizing structure-guided scaffold-hopping strategy. The dihydrofuro[3,4-d]pyrimidine 13c2 13c4 proved be exceptionally potent against wide range strains carrying single NNRTI-resistant mutations (EC50 = 0.9–8.4 nM), which remarkably superior that etravirine...
The development of efficacious NNRTIs for AIDS therapy commonly encountered the rapid generation drug-resistant mutations, which becomes a major impediment to effective anti-HIV treatment. Using structure-based bioisosterism strategy, series piperidine-substituted thiophene[2,3-d]pyrimidine derivatives were designed and synthesized. Compound 9a yielded greatest potency, exhibiting significantly better anti-HIV-1 activity than ETR against all tested NNRTI-resistant HIV-1 strains. In addition,...
In this report, a series of novel piperidine-substituted thiophene[3,2-d]pyrimidine derivatives were designed to explore the hydrophobic channel non-nucleoside reverse transcriptase inhibitors binding pocket (NNIBP) by incorporating an aromatic moiety left wing lead K-5a2. The newly synthesized compounds evaluated for anti-HIV potency in MT-4 cells and inhibitory activity HIV-1 (RT). Most exhibited broad-spectrum toward wild-type wide range strains carrying single (NNRTI)-resistant...
Our previous efforts have led to the development of two potent NNRTIs, K-5a2 and 25a, exhibiting effective anti-HIV-1 potency resistance profiles compared with etravirine. However, both inhibitors suffered from hERG inhibition short half-life. In this article, etravirine as leads, series novel fluorine-substituted diarylpyrimidine derivatives were designed via molecular hybridization bioisosterism strategies. The results indicated 24b was most active inhibitor, broad-spectrum activity (EC50...
There is an urgent unmet medical need for novel human immunodeficiency virus type 1 (HIV-1) inhibitors that are effective against a variety of NNRTI-resistance mutations. We report our research efforts aimed at discovering chemotype anti-HIV-1 agents with improved potency mutations in this paper. Structural modifications the lead K-5a2 led to identification potent inhibitor 16c. 16c yielded highly activities and resistance profiles compared approved drug etravirine. The co-crystal structure...
Abstract HIV-1 reverse transcriptase offers a key target for antiviral therapy. However, the rapid emergence of drug-resistant mutations in as well poor pharmacokinetic properties non-nucleoside inhibitors (NNRTIs) limits their clinical use. Starting from previous piperidine-substituted thiophene[3,2- d ]pyrimidine compound (K-5a2), here we explore chemical space around thiophene ring located solvent-exposed regions NNRTI binding pocket detail. Bioisosterism-based structural modification...
The persistence of HIV-1 in a latent state within long-lived immune cells remains major barrier to cure for infection. "block-and-lock" strategy aims silence the provirus permanently using latency promoting agents (LPAs). LEDGINs, well-known class LPAs, inhibit interaction between viral integrase and LEDGF/p75, reducing integration retargeting regions resistant reactivation. However, proximity enhancers may still permit residual transcription. Given BRD4's central role enhancer biology, we...
Our previous studies led us to conclude that thiophene[3,2-d]pyrimidine is a promising scaffold for diarylpyrimidine (DAPY)-type anti-HIV agents with potent activity against resistance-associated human immunodeficiency virus (HIV) variants (J. Med. Chem. 2016, 59, 7991–8007; J. 2017, 60, 4424–4443). In the present study, we designed and synthesized series of thiophenepyrimidine derivatives various substituents in right wing region structure aim developing new interactions tolerant I binding...
Based on the detailed analysis of binding mode diarylpyrimidines (DAPYs) with HIV-1 RT, we designed several subseries novel NNRTIs, aim to probe biologically relevant chemical space solvent-exposed tolerant regions in NNRTIs pocket (NNIBP). The most potent compound 21a exhibited significant activity against whole viral panel, being about 1.5–2.6-fold (WT, EC50 = 2.44 nM; L100I, 4.24 Y181C, 4.80 F227L + V106A, 17.8 nM) and 4–5-fold (K103N, 1.03 Y188L, 7.16 E138K, 3.95 more than reference drug...
Etravirine (ETV) was approved as the second generation drug for use in individuals infected with HIV-1 2008 by U.S. FDA its unique antiviral activity, high specificity, and low toxicity. However, there are some shortcomings of existing synthetic routes, such long reaction time poor yield.This article describes our efforts to develop an efficient, practical, microwave-promoted method one key intermediate ETV, which is capable being operated on a scale-up synthesis level. Through this...
Here, we report the design, synthesis, structure–activity relationship studies, antiviral activity, enzyme inhibition, and druggability evaluation of dihydrofuro[3,4-d]pyrimidine derivatives as a potent class HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Compounds 14b (EC50 = 5.79–28.3 nM) 16c 2.85–18.0 exhibited superior potency against panel HIV-1-resistant strains. Especially, for changeling mutations F227L/V106A K103N/Y181C, both compounds remarkably improved activity...
Abstract In the previous studies of our laboratory, thiophene[3,2‐ d ]pyrimidine was identified as a promising scaffold for seeking highly potent HIV ‐1 non‐nucleoside reverse transcriptase inhibitors ( NNRTI s). this study, we designed, synthesized, and biologically evaluated series derivatives with changed linker between thiophenepyrimidine core right wing. Some synthesized compounds exhibited excellent inhibitory potency low (double‐digit) nanomolar 50% effective concentration EC 50 )...
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) represent an indispensable part of anti-HIV-1 therapy. To discover novel HIV-1 NNRTIs with increased drug resistance profiles and improved pharmacokinetic (PK) properties, a series diarylpyrimidine derivatives were generated via the cocrystal structure-based design strategy. Among them, 36a exhibited outstanding antiviral activity against IIIB panel mutant strains (L100I, K103N, Y181C, Y188L, E138K, F227L + V106A, RES056), EC50 ranging...
Abstract Two novel series of human immunodeficiency virus‐1 ( HIV ‐1) non‐nucleoside reverse transcriptase inhibitors NNRTI s) bearing a thiophene[3,2‐ d ]pyrimidine scaffold and sulfonamide linker in the right wing have been identified, which demonstrated activity against wild‐type WT ) ‐1 strain MT ‐4 cells with inhibitory concentrations ranging from micromolar to submicromolar. Especially, mutant strains K103N E138K, most compounds exhibited more potent than ‐1. Compound 7 EC 50 = 0.014,...
Previous efforts in our lab have led to the development of human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase inhibitor (NNRTI) thiophene[3,2-d]pyrimidine compound (K-5a2) with promising activity against wild-type and mutant HIV-1 strains. In this work, a series novel diarylpyrimidines derivatives carrying structurally diverse motif at right wing lead K-5a2 was designed synthesized as potential anti-HIV-1 agents. The results demonstrated that 8a yielded...