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Inspired by our previous work on the modification of diarylpyrimidine-typed non-nucleoside reverse transcriptase inhibitors (NNRTIs) and the reported crystallographic studies, a series of novel amino acids (analogues)-substituted thiophene[3,2-d]pyrimidine derivatives were designed and synthesized by targeting the solvent-exposed region of the NNRTI-binding pocket. The biological evaluation results showed that compound 5k was the most active inhibitor, exhibiting moderate-to-excellent potency against HIV-1 wild-type (WT) and a panel of NNRTI-resistant strains, with EC50 values ranging from 0.042 μM to 7.530 μM. Of special note, 5k exhibited the most potent activity against single-mutant strains (K103N and E138K), with EC50 values of 0.031 μM and 0.094 μM, being about 4.3-fold superior to EFV (EC50 = 0.132 μM) and 1.9-fold superior to NVP (EC50 = 0.181 μM), respectively. In addition, 5k demonstrated lower cytotoxicity (CC50 = 27.9 μM) and higher selectivity index values. The HIV-1 reverse transcriptase (RT) inhibition assay was further performed to confirm their binding target. Moreover, preliminary structure–activity relationships (SARs) and molecular docking studies were also discussed in order to provide valuable insights for further structural optimizations. In summary, 5k turned out to be a promising NNRTI lead compound for further investigations of treatments for HIV-1 infections. [ABSTRACT FROM AUTHOR]

In addressing the urgent need for novel HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) to combat drug resistance, we employed CuAAC click chemistry to construct a diverse 312-member diarylpyrimidine (DAPY) derivative library. This rapid synthesis approach facilitated the identification of A6N36 , demonstrating exceptional HIV-1 RT inhibitory activity. Moreover, it was demonstrated with EC 50 values of 1.8–8.7 nM for mutant strains L100I, K103 N, Y181C, and E138K, being equipotent or superior to that of ETR. However, A6N36 's efficacy was compromised against specific resistant strains (Y188L, F227L + V106A and RES056), highlighting a need for further optimization. Through scaffold hopping, we optimized this lead to develop 10c , which exhibited broad-spectrum activity with EC 50 values ranging from 3.2 to 57.5 nM and superior water solubility. Molecular docking underscored the key interactions of 10c within the NNIBP. Our findings present 10c as a promising NNRTI lead, illustrating the power of click chemistry and rational design in combatting HIV-1 resistance. [Display omitted] • CuAAC click chemistry was employed to construct a diverse 312-member diarylpyrimidine (DAPY) derivative library. • 10c demonstrated promising antiviral activity against both IIIB strain and mutant strains of HIV-1. • 10c displayed significantly improved water solubility compared with ETR and RPV. • Molecular modeling studies of 10c with NNIBP provided insights into the mechanisms of drug resistance. [ABSTRACT FROM AUTHOR]

In the previous studies of our laboratory, the thiophene[3,2‐d]pyrimidine was identified as a promising scaffold for seeking highly potent HIV‐1 non‐nucleoside reverse transcriptase inhibitors (NNRTIs). In this study, we designed, synthesized, and biologically evaluated a series of thiophene[3,2‐d]pyrimidine derivatives with changed linker between the thiophenepyrimidine core and the right wing. Some of the synthesized compounds exhibited excellent HIV‐1 inhibitory potency with low (double‐digit) nanomolar 50% effective concentration (EC50) values. Among them, compound 13a exhibited the most potent anti‐HIV‐1 activity (EC50 = 21.2 nM), which was 10‐fold greater than that of NVP (EC50 = 281 nM). Moreover, 13a showed much lower cytotoxicity (CC50 = 183 μM) and higher selection index (SI = 8,632) than NVP, ETV, and AZT. Besides, some physicochemical properties and water solubility were calculated or measured. The preliminary structure–activity relationships and molecular simulation studies of these compounds were also discussed comprehensively to provide valuable direction for further design and optimization. In the present study, we designed, synthesized, and biologically evaluated a series of thiophene[3,2‐d]pyrimidine derivatives bearing the hydrazone linker between the thiophenepyrimidine core and the right wing. In particular, compound 13a exhibited the most potent anti‐HIV‐1 activity. Besides, some physicochemical properties and water solubility were calculated or measured. The preliminary structure–activity relationships and molecular simulation studies of these compounds were also discussed comprehensively to provide valuable direction for further design and optimization. [ABSTRACT FROM AUTHOR]

HIV-1 reverse transcriptase offers a key target for antiviral therapy. However, the rapid emergence of drug-resistant mutations in reverse transcriptase as well as the poor pharmacokinetic properties of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) limits their clinical use. Starting from a previous piperidine-substituted thiophene[3,2-d]pyrimidine compound (K-5a2), here we explore the chemical space around the thiophene ring located in the solvent-exposed regions of the NNRTI binding pocket in detail. Bioisosterism-based structural modification leads to the discovery of a number of compounds as potent in vitro reverse transcriptase inhibitors, providing improved drug resistance profiles compared to the listed drug Etravirine. Furthermore, 14a and 19a are identified as lead compounds with good solubility, appropriate ligand efficiency, and lower cytochrome P450 liability. Compound 19a exhibits useful in vivo pharmacokinetic properties in rat and safety in mice, suggesting that it may have the potential to be an effective drug candidate for treating AIDS. Current non-nucleoside reverse transcriptase inhibitors can be limited by poor solubility and hence bioavailability. Here, bioisosteric replacement from a known lead compounds yields new, active candidates with improved aqueous solubility. [ABSTRACT FROM AUTHOR]

Inspired by our previous efforts to improve the drug-resistance profiles of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), a novel series of "dual-site" binding diarylpyrimidine (DAPY) derivatives targeting both the NNRTI adjacent site and NNRTIs binding pocket (NNIBP) were designed, synthesized, and evaluated for their anti -HIV potency in TZM-bl and MT-4 cells. Eight compounds exhibited moderate to excellent potencies in inhibiting wild-type (WT) HIV-1 replication with EC 50 values ranging from 2.45 nM to 5.36 nM, and 14c (EC 50 = 2.45 nM) proved to be the most promising inhibitor. Of note, 14c exhibited potent activity against the single mutant strain E138K (EC 50 = 10.6 nM), being comparable with ETR (EC 50 = 9.80 nM) and 3.5-fold more potent than that of compound 7 (EC 50 = 37.3 nM). Moreover, 14c acted as a classical NNRTI with high affinity for WT HIV-1 RT (IC 50 = 0.0589 μM). The detailed structure-activity relationships (SARs) of the representative compounds were also determined, and further supported by molecular dynamics simulation. Overall, we envision that the "dual-site"-binding NNRTIs have significant prospects and pave the way for the next round of rational design of potent anti -HIV-1 agents. Image 1 • A series of "dual-site" binding diarylpyrimidine derivatives were discovered. • Trans -double bond with spatial orientation advantage was introduced. • 14c turned out to be potent inhibitor against single mutation strain E138K. • 14c acted as classical NNRT inhibitors with high affinity for WT HIV-1 RT. • 14c and 17l are proposed as promising inhibitors by MD simulation. [ABSTRACT FROM AUTHOR]