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3,3a-Dihydropyrano[4,3,2-de]quinazolin-2(1H)-ones are potent non-nucleoside reverse transcriptase inhibitors
J W Corbett1, S Pan, J A Markwalder
1DuPont Pharmaceuticals Company, Experimental Station, Wilmington, DE 19880-0500, USA. jeffrey.w.corbett@am.pnu.com
Bioorganic & Medicinal Chemistry Letters
|February 24, 2001
Summary
New quinazolinone derivatives show promise as HIV-1 non-nucleoside reverse transcriptase inhibitors. One compound demonstrated potent activity against wild-type HIV-1, with moderate activity against key drug-resistant mutations.
Area of Science:
- Medicinal Chemistry
- Virology
- Organic Synthesis
Background:
- Human Immunodeficiency Virus type 1 (HIV-1) remains a significant global health challenge.
- Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are a crucial class of antiretroviral drugs.
- Development of novel NNRTIs is essential to combat drug resistance and improve treatment efficacy.
Purpose of the Study:
- To synthesize and evaluate novel heterocyclic compounds as potential HIV-1 NNRTIs.
- To assess the antiviral activity of these compounds against wild-type and mutant HIV-1 strains.
Main Methods:
- Synthesis of a series of unique 3,3a-dihydropyrano[4,3,2-de]quinazolin-2(1H)-ones and a 2a,5-dihydro-2H-thieno[4,3,2-de]quinazo-line-4(3H)-thione.
- Antiviral assays were performed using whole cell systems to determine inhibitory concentrations (IC50).
Main Results:
- Several synthesized compounds exhibited activity as HIV-1 NNRTIs.
- One compound, tested as a racemate, showed potent inhibition of wild-type HIV-1 with an IC90 of 4.6 nM.
- This compound displayed IC90 values of 76 nM against the K103N mutant and 897 nM against the K103N/L100I double mutant virus.
Conclusions:
- The novel quinazolinone and thienoquinazoline derivatives represent a promising scaffold for HIV-1 NNRTI development.
- The lead compound exhibits significant potency against wild-type HIV-1 and retains some activity against common resistance mutations.