ArticleBioorganic & medicinal chemistry2017
An integrated chemical biology approach reveals the mechanism of action of HIV replication inhibitors.
Article in Bioorganic & medicinal chemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- Targeting Breast Cancer: Novel Dihydropyrimidinones As Potent Eg5 Inhibitors.Medicinal chemistry (Shariqah (United Arab Emirates)) · 2025Article
- Designing and the anticancer activity of chitosan and chitosan oligosaccharide lactate nanobeads loaded with Biginelli hybrid.RSC advances · 2024Article
- The Medicinal Chemistry in the Era of Machines and Automation: Recent Advances in Continuous Flow Technology.Journal of medicinal chemistry · 2020Review
- Exploiting the Nucleophilicity of the Nitrogen Atom of Imidazoles: One-Pot Three-Component Synthesis of Imidazo-Pyrazines.Molecules (Basel, Switzerland) · 2019Article
- Synthesis, Characterization, and Anticancer Activities Evaluation of Compounds Derived from 3,4-Dihydropyrimidin-2(1Molecules (Basel, Switzerland) · 2019Article
- A Combination of Flow and Batch Mode Processes for the Efficient Preparation of mGluTetrahedron · 2018Article
- Molecular Docking Studies of HIV-1 Resistance to Reverse Transcriptase Inhibitors: Mini-Review.Molecules (Basel, Switzerland) · 2018Review
- Automating drug discovery.Nature reviews. Drug discovery · 2018Review
Corrections and comments
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Authors and funding
8 authors.
Funding
Abstract
Continuous flow (microfluidic) chemistry was employed to prepare a small focused library of dihydropyrimidinone (DHPM) derivatives. Compounds in this class have been reported to exhibit activity against the human immunodeficiency virus (HIV), but their molecular target had not been identified. We tested the initial set of DHPMs in phenotypic assays providing a hit (1i) that inhibited the replication of the human immunodeficiency virus HIV in cells. Flow chemistry-driven optimization of 1i led to the identification of HIV replication inhibitors such as 1l with cellular potency comparable with the clinical drug nevirapine (NVP). Mechanism of action (MOA) studies using cellular and biochemical assays coupled with 3D fingerprinting and in silico modeling demonstrated that these drug-like probe compounds exert their effects by inhibiting the viral reverse transcriptase polymerase (RT). This led to the design and synthesis of the novel DHPM 1at that inhibits the replication of drug resistant strains of HIV. Our work demonstrates that combining flow chemistry-driven analogue refinement with phenotypic assays, in silico modeling and MOA studies is a highly effective strategy for hit-to-lead optimization applicable to the discovery of future therapeutic agents.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.