Related Experiment Video
Updated: Mar 16, 2026
Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
Design, Synthesis, and Evaluation of Thiophene[3,2-d]pyrimidine Derivatives as HIV-1 Non-nucleoside Reverse
Dongwei Kang1, Zengjun Fang1,2, Zhenyu Li1
1Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University , 44 West Culture Road, Jinan 250012, Shandong P.R. China.
New non-nucleoside reverse transcriptase inhibitors (NNRTIs) show potent activity against various human immunodeficiency virus type 1 (HIV-1) strains. Compound 27 demonstrates significant antiviral efficacy and favorable safety profiles, offering promise for HIV-1 treatment.
Area of Science:
- Medicinal Chemistry
- Virology
- Drug Discovery
Background:
- Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are crucial in managing HIV-1 infection.
- Development of NNRTIs effective against drug-resistant HIV-1 strains remains a priority.
- Piperidine-substituted thiophene[3,2-d]pyrimidine scaffolds represent a potential platform for novel NNRTI design.
Purpose of the Study:
- To design and synthesize novel human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase inhibitors (NNRTIs).
- To evaluate the antiviral activity and cytotoxicity of the synthesized compounds against wild-type and mutant HIV-1 strains.
- To investigate the structure-activity relationships and pharmacokinetic properties of potent compounds.
Main Methods:
- Structure-based molecular hybridization and substituent decorating strategies were employed for compound design.
- Antiviral activity was assessed using EC50 values against various HIV-1 strains (wild-type, single and double mutants).
- Cytotoxicity was determined by CC50 values, and selectivity index (SI) was calculated. In vivo pharmacokinetic and safety studies were conducted in rats.
Main Results:
- A series of piperidine-substituted thiophene[3,2-d]pyrimidine derivatives were synthesized.
- Most compounds displayed broad-spectrum antiviral activity with low nanomolar EC50 values.
- Compound 27 exhibited superior potency and efficacy compared to ETV against multiple HIV-1 variants, with excellent safety (CC50 > 227 μM) and a high SI (>159101).
- Compound 27 demonstrated favorable drug-like pharmacokinetic and safety profiles in vivo.
Conclusions:
- The synthesized piperidine-substituted thiophene[3,2-d]pyrimidine derivatives are promising candidates for novel HIV-1 NNRTIs.
- Compound 27 stands out as a highly potent and safe NNRTI with potential for further development.
- Molecular docking and SAR studies provide valuable insights for optimizing future drug candidates.
