Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 63, Issue 9, Pages 4837-4848Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c00117
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Funding
- National Natural Science Foundation of China (NSFC) [81973181, 81903453]
- Key Project of NSFC for International Cooperation [81420108027]
- Shandong Provincial Natural Science Foundation [ZR2019BH011]
- China Postdoctoral Science Foundation [2019T120596]
- Young Scholars Program of Shandong University (YSPSDU) [2016WLJH32]
- Shandong Provincial Key research and development project [2017CXGC1401, 2019JZZY021011]
- Taishan Scholar Program at Shandong Province
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The development of efficacious NNRTIs for AIDS therapy commonly encountered the rapid generation of drug-resistant mutations, which becomes a major impediment to effective anti-HIV treatment. Using a structure-based bioisosterism strategy, a series of piperidine-substituted thiophene[2,3-d]pyrimidine derivatives were designed and synthesized. Compound 9a yielded the greatest potency, exhibiting significantly better anti-HIV-1 activity than ETR against all of the tested NNRTI-resistant HIV-1 strains. In addition, the phenotypic (cross)resistance of 9a and other NRTIs to the different selected HIV-1 strains was evaluated. As expected, no phenotypic cross-resistance against the NRTIs (AZT and PMPA) was observed with the mutant 9a(res) strain. Furthermore, 9a was identified with improved solubility, lower CYP liability, and hERG inhibition. Remarkably, 9a exhibited optimal pharmacokinetic properties in rats (F = 37.06%) and safety in mice (LD50 > 2000 mg/kg), which highlights 9a as a promising anti-HIV-1 drug candidate.
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