Anti-AIDS agents 79. Design, synthesis, molecular modeling and structure–activity relationships of novel dicamphanoyl-2′,2′-dimethyldihydropyranochromone (DCP) analogs as potent anti-HIV agents

Abstract

In a continued study, 23 3′R,4′R-di-O-(−)-camphanoyl-2′,2′-dimethyldihydropyrano[2,3-f]chromone (DCP) derivatives (5–27) were synthesized, and screened for anti-HIV activity against both a non-drug-resistant NL4-3 strain and multiple reverse transcriptase (RT) inhibitor-resistant (RTMDR-1) strain, using 2-EDCP (4) and 2-MDCP (35) as controls. New DCP analogs 5, 9, 14, and 22 exhibited potent anti-HIV activity against HIVNL4-3 with EC50 and therapeutic index (TI) values ranging from 0.036μM to 0.14μM and from 110 to 420, respectively. Compounds 5 and 9 also exhibited good activity against RTMDR-1 (EC50 0.049 and 0.054μM; TI 310 and 200, respectively), and were twofold more potent than the leads 4 and 35 (EC50 0.11 and 0.19μM; TI 60 and 58, respectively). Evaluation of water solubility showed that 5 and 22 were 5–10 times more water soluble than 4. Quantitative structure–activity relationship (QSAR) modeling results were first performed on this compound type, and the models should aid in design of future anti-HIV DCP analogs and potential clinical drug candidates.