Discovery of Novel Dihydrothiopyrano[4,3-d]pyrimidine Derivatives as Potent HIV-1 NNRTIs with Significantly Reduced hERG Inhibitory Activity and Improved Resistance Profiles

Abstract

Enlightened by the available structural biology information, a novel series of dihydrothiopyrano­[4,3-d]­pyrimidine derivatives were rationally designed via scaffold hopping and molecular hybridization strategies. Notably, compound 20a yielded exceptionally potent antiviral activities (EC50 = 4.44–54.5 nM) against various HIV-1 strains and improved resistance profiles (RF = 0.5–5.6) compared to etravirine and rilpivirine. Meanwhile, 20a exhibited reduced cytotoxicity (CC50 = 284 μM) and higher SI values (SI = 5210–63992). Molecular dynamics simulations were performed to rationalize the distinct resistance profiles. Besides, 20a displayed better solubility (sol. = 12.8 μg/mL) and no significant inhibition of the main CYP enzymes. Furthermore, 20a was characterized for prominent metabolic stability and in vivo safety properties. Most importantly, the hERG inhibition profile of 20a (IC50 = 19.84 μM) was a remarkable improvement. Overall, 20a possesses huge potential to serve as a promising drug candidate due to its excellent potency, low toxicity, and favorable drug-like properties.

Discovery of Novel Pyridine-Dimethyl-Phenyl-DAPY Hybrids by Molecular Fusing of Methyl-Pyrimidine-DAPYs and Difluoro-Pyridinyl-DAPYs: Improving the Druggability toward High Inhibitory Activity, Solubility, Safety, and PK

“…The target compounds were mainly synthesized via the Suzuki–Miyaura cross-coupling. The key intermediate 6 and 8 were prepared from 2-mercapto-5-methylpyrimidin-4-ol or 2-mercaptopyrimidin-4-ol according to a four-step protocol which was reported in our previous articles. ,,− For compounds 7a – l , compound 6 reacted with various heterocyclic borates to afford the target compounds in the yield of 58–93%. Similarly, various heterocyclic borates were reacted with 8 to obtain the target compounds 9a – t in the yield of 66–95%.…”

“…Noticeably, 7a·HBr significantly improved the stability in human liver microsomes (Cl int = 14.6 μL/min/mg proteins, T 1/2 = 95 min) and displayed a suitable clearance and a longer half-life, which were comparable to 3 . Furthermore, a single-dose acute toxicity of 7a·HBr was detected according to our established protocol. , No death occurred after intragastric (i.g.) administration of 7a·HBr at a high dose of 2 g/kg.…”

Design and Characterization of a Natural Arf-GEFs Inhibitor Prodrug CHNQD-01255 with Potent Anti-Hepatocellular Carcinoma Efficacy In Vivo

“…The potent hERG channel inhibition by noncardiovascular medications could trigger the blockade of rapid delayed rectifier potassium current ( I Kr ), leading to the drug-induced QT interval prolongation with the increased risks of cardiac arrest. , Owing to the detectable concentrations in the heart as described in the tissue distribution assay (Figure ), the potential heart toxicity of CHNQD-01255 was investigated with electrophysiology functional human ether-a-go-go-related gene (hERG) assay with a patch clamp. As depicted in Figure S119, extremely low hERG inhibition (IC 50 > 30 μM, quinidine as a positive control) indicated a low risk of cardiotoxicity.…”

Newly Emerging Strategies in Antiviral Drug Discovery: Dedicated to Prof. Dr. Erik De Clercq on Occasion of His 80th Anniversary

“…Undoubtedly, our endeavors and most achievements in antiviral drug research field have continuously benefited from the inspiration of these articles and his direct guidance. Our long-term close cooperation with Professor Erik De Clercq culminated in the discovery of several antiviral drug candidates for further preclinical studies or clinical trials [ 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 ]. On the occasion of his 80th anniversary, on behalf of our whole research group, we would like to extend our sincere gratitude and best wishes to Professor Erik De Clercq.…”