Guoming Zhao

2,4-Diaryl-4,6,7,8-tetrahydroquinazolin-5(1H)-one derivatives as anti-HBV agents targeting at capsid assembly

A series of novel 2,4-diaryl-4,6,7,8-tetrahydroquinazolin-5(1H)-one derivatives were designed and synthesized as potent inhibitors of HBV capsid assembly. These compounds arose from efforts to rigidify an earlier series of heteroaryldihydropyrimidines (HAPs), and compounds 12, 13, 20, 24, 30 and 32 showed potent inhibition of HBV capsid assembly, especially 24 with IC(50) value at sub-micromolar range.

Novel fatty acid synthase (FAS) inhibitors: Design, synthesis, biological evaluation, and molecular docking studies

Several novel series of C75 derivatives were synthesized and evaluated for their FAS inhibitory activities. The results showed compound 4-methylene-2-octyl-5-oxo-tetrahydro-thiophene-3-carboxylic acid (1c) had more effective FAS inhibitory (IC(50) was 2.56 microM and T.I. was 9.26) and potent anti-tumor activities on HL60 and Hela cells in vitro (IC(50) were 5.38 microM and 46.10 microM, respectively).

A new series of HAPs as anti-HBV agents targeting at capsid assembly.

A series of novel Heteroaryldihydropyrimidines (HAPs) derivatives were designed and synthesized as potent inhibitors of HBV capsid assembly. These compounds were prepared from efforts to optimize an earlier series of HAPs, and compounds Mo1, Mo7, Mo8, Mo10, Mo12, and Mo13 demonstrated potent inhibition of HBV DNA replication at submicromolar range.

1-Oxo-3-substitute-isothiochroman-4-carboxylic acid compounds: Synthesis and biological activities of FAS inhibition

A new series 1-oxo-3-substitute-isothiochroman-4-carboxylic acid compounds have been designed and synthesized. Screening of these molecules for FAS inhibition in vitro has indicated that compounds 2c and 2d showed more effective FAS inhibition activities and higher therapeutic index than C75.

The novel compound Z060228 inhibits assembly of the HBV capsid.

AIMS The effective anti-HBV drugs on the market are mainly immunomodulators or nucleoside analogs. The uses of INF-α and lamivudine (3TC) are considerably limited by their low response rate, side effects, drug resistance and HBV recurrence. Thus, new mechanism-based drugs remain in urgent need. This study aimed to investigate the anti-HBV effects of the novel compound Z060228 and to confirm its anti-HBV mechanisms. MAIN METHODS HepG2.2.15 cells and HBV-transgenic mice were used to evaluate the anti-HBV activity of Z060228. Conformational changes of the capsid structure induced by Z060228 were detected with high-resolution electron microscopy (EM), size-exclusion chromatography (SEC), and atomic force microscopy (AFM). KEY FINDINGS The HBV DNA replication in the supernatants of the HepG2.2.15 cells was effectively inhibited by Z060228 and Bay41-4109. In the liver of HBV-transgenic mice, the HBcAg content was significantly decreased and HBV DNA replication was also inhibited after high-dose (30 mg/kg) Z060228 treatment. Z060228 and Bay41-4109 exhibited similar effects on the self-assembly of Cp149. SEC data revealed that Z060228 altered the equilibrium (a state of stability) of Cp149 assembly. EM data further demonstrated that Z060228 could prevent Cp149 from self-assembling to the correct core particles. Additionally, AFM results showed that a low concentration of Z060228 caused Cp149 syncretizing, whereas a high concentration caused Cp149 to polymerize. SIGNIFICANCE Z060228 was demonstrated to be a potential capsid targeting anti-HBV drug candidate. The methods employed here could be used as a general strategy to study mechanisms of self-assembling protein-targeted drugs.

An Efficient Synthesis of Enantiopure (R)-heteroarylpyrimidine Analogs

An efficient synthesis of enantiopure (R)-heteroarylpyrimidine analogs is described here, which involves introduction of a chiral group, formation and separation of diasteroisomers and final transformation of an amide to an ester. The absolute configuration of the enantiopure HAPs is confirmed by X-ray analysis of their intermediates.

Facile One-Pot Method for the Synthesis of Polysubstituted Phthalide Derivatives

Abstract A new three-component cyclization method is described involving two starting materials, ethyl 4-chloroacetoacetate and aldehydes, catalyzed by piperidine, acid, and iodine. Ten corresponding polysubstituted phthalides are formed with good yields (44–78%). A mechanism of the reaction is also proposed. GRAPHICAL ABSTRACT