Amino acid prodrugs of NVR3-778: Design, synthesis and anti-HBV activity.

A series of amino acid prodrugs of NVR3-778, a potent anti-HBV candidate currently under phase II clinical trial, were designed and synthesized as new anti-HBV agents. Except for 1e, all of them displayed roughly comparable anti-HBV activity (IC50, 0.28-0.56 µM) to NVR3-778 (IC50, 0.26 µM). Compound 1a, a l-valine ester prodrug of NVR3-778, was found to show significantly improved water solubility (0.7 mg/mL, pH 2) as we expected, and lower cytotoxicity (CC50 > 10 µM) than NVR3-778 (CC50, 4.81 µM). Moreover, 1a also exhibited acceptable PK properties and comparable in vivo efficacy in HBV DNA hydrodynamic mouse model to that of NVR3-778, suggesting it may serve as a promising lead compound for further anti-HBV drug discovery.

Design, synthesis and anti-HBV activity of NVR3-778 derivatives.

NVR3-778, one of the most advanced capsid assembly modulators (CAMs), is currently in phase II clinical trial for the treatment of HBV infection. In this study, we reported the first structure optimization of NVR3-778. Compound 2d was found to exhibit more potent anti-HBV activity (IC50: 0.25 µM), lower cytotoxicity (CC50: 10.68 µM) and higher selectivity index (SI: 40.72) than NVR3-778 (IC50: 0.33 µM; CC50: 5.14 µM; SI: 18.36) in vitro, and also display similar inhibitory effect on the assembly of HBV capsids as NVR3-778. Molecular docking further suggested that compound 2d might form a stronger interaction with core protein. Moreover, compound 2d also showed acceptable pharmacokinetic profiles. Currently compound 2d was selected as a new lead for further modifications, and studies to determine the in vivo anti-HBV studies of 2d will begin soon.

Design, synthesis and antimycobacterial activity of less lipophilic Q203 derivatives containing alkaline fused ring moieties.

We report herein the design and synthesis of a series of less lipophilic Q203 derivatives containing an alkaline fused ring moiety. Most of them show considerable potency against MTB H37Rv strain (MIC < 0.25 µM). Nine compounds (13, 15, 19, 21, 23, 25, 29, 35, 36) have the same excellent activity against both drug-sensitive and -resistant strains (MIC < 0.035 µM) as Q203 and PBTZ169. Especially, compound 29 also displays acceptable safety, greater absorption in plasma and aqueous solubility than Q203, suggesting its promising potential to be lead compound for future antitubercular drug discovery.

Design, synthesis and in vitro anti-Zika virus evaluation of novel Sinefungin derivatives.

We report herein the design and synthesis of a series of novel Sinefungin (SIN) derivatives, based on the structures of SIN and its analogue EPZ004777. Our results reveal that target compounds 1ad-af, 1ba-bb and 1bf-bh show better activity (IC50 = 4.56-20.16 µM) than EPZ004777 (IC50 = 35.19 µM). Surprisingly, SIN was founded to be not as active (IC50 > 50 µM) as we and other research groups predicted. Interestingly, the intermediates 9a-b and 11b display potent anti-ZIKV potency (IC50 = 6.33-29.98 µM), and compound 9a also exhibits acceptable cytotoxicity (CC50 > 200 µM), suggesting their promising potential to be leads for further development.

Identification of N-Benzyl 3,5-Dinitrobenzamides Derived from PBTZ169 as Antitubercular Agents.

A series of benzamide scaffolds were designed and synthesized by the thiazinone ring opening of PBTZ169, and N-benzyl 3,5-dinitrobenzamides were finally identified as anti-TB agents in this work. 3,5-Dinitrobenzamides D5, 6, 7, and 12 exhibit excellent in vitro activity against the drug susceptive Mycobacterium tuberculosis H37Rv strain (MIC: 0.0625 µg/mL) and two clinically isolated multidrug-resistant strains (MIC < 0.016-0.125 µg/mL). Compound D6 displays acceptable safety and better pharmacokinetic profiles than PBTZ169, suggesting its promising potential to be a lead compound for future antitubercular drug discovery.