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In this study, a novel series of diarylpyrimidine derivatives with Fsp3‐enriched spirocycles were designed and synthesized to further explore the chemical space of the hydrophobic channel of the NNRTI‐binding pocket. The biological evaluation results showed that most of the compounds displayed effective inhibitory potency against the HIV‐1 wild‐type strain, with EC50 values ranging from micromolar to submicromolar levels. Among them, TT6 turned out to be the most effective inhibitor with an EC50 value of 0.17 μM, demonstrating up to 47 times more active than that of reference drug 3TC (EC50 = 8.01 μM). More encouragingly, TT6 was found to potently inhibit the HIV‐1 mutant strain K103N with an EC50 value of 0.69 μM, being about 6‐fold more potent than 3TC (EC50 = 3.68 μM) and NVP (EC50 = 4.62 μM). Furthermore, TT6 exhibited the most potent inhibitory activity toward HIV‐1 reverse transcriptase with an IC50 value of 0.33 μM. Additionally, molecular simulation studies were conducted to investigate the binding modes between TT6 and NNRTI‐binding pocket, which may provide valuable clues for the follow‐up structural optimizations. [ABSTRACT FROM AUTHOR]

With our continuous endeavors in seeking potent anti-HIV-1 agents, we reported here the discovery, biological characterization, and druggability evaluation of a class of nonnucleoside reverse transcriptase inhibitors. To fully explore the chemical space of the NNRTI-binding pocket, novel series of dihydrothiopyrano [3,2- d ]pyrimidines were developed by employing the structure-based design strategy. Most of the derivatives were endowed with prominent antiviral activities against HIV-1 wild-type and resistant strains at nanomolar levels. Among them, compound 23h featuring the aminopiperidine moiety was identified as the most potent inhibitor, with EC 50 values ranging from 3.43 to 21.4 nmol/L. Especially, for the challenging double-mutants F227L + V106A and K103N + Y181C, 23h exhibited 2.3- to 14.5-fold more potent activity than the first-line drugs efavirenz and etravirine. Besides, the resistance profiles of 23h achieved remarkable improvement compared to efavirenz and etravirine. The binding target of 23h was further confirmed to be HIV-1 reverse transcriptase. Molecular modeling studies were also performed to elucidate the biological evaluation results and give guidance for the optimization campaign. Furthermore, no apparent inhibition of the major CYP450 enzymes and hERG channel was observed for 23h. Most importantly, 23h was characterized by good pharmacokinetic properties and excellent safety in vivo. Collectively, 23h holds great promise as a potential candidate for its effective antiviral efficacy and favorable drug-like profiles. With our continuous endeavors in seeking potent anti-HIV-1 agents, we report here the discovery of 23h as a potential candidate due to its prominent antiviral activities and favorable druggability profiles. [Display omitted] [ABSTRACT FROM AUTHOR]