Discovery of DC20 as a potential non-nucleoside reverse transcriptase inhibitor with excellent pharmacokinetic properties

Abstract

S-DACOs are a series of non-nucleoside reverse transcriptase inhibitors (NNRTIs) known for their effective antiviral activity and low cytotoxicity, although their water solubility and bioavailability have been suboptimal. In this study, we synthesized and evaluated 25 novel compounds, most of which demonstrated a CLogP below 5 and exhibited potent antiviral activity against HIV-1_IIIB with EC₅₀ values ranging from 0.86 to 0.004 μmol/L. Among them, compound DC20 (EC₅₀ = 0.004 μM, CC₅₀ = 134.21 ± 0.78 μM, SI = 33,552) emerged as particularly promising, it effectively targets reverse transcriptase and maintains high efficacy against mutant strains V106M, K103N, and Y181C. Particularly notable is that DC20 possesses excellent pharmacokinetic properties, with an oral bioavailability reaching up to 89.1 %. Given its high potency and low toxicity, DC20 holds significant potential for drug development and may serve as a critical candidate for future clinical applications. Further investigations will focus on its pharmaceutical viability.