3D-QSAR studies of heterocyclic quinones with inhibitory activity on vascular smooth muscle cell proliferation using pharmacophore-based alignment.

The abnormal proliferation and migration of vascular smooth muscle cells (SMCs) play an important role in the pathology of coronary artery atherosclerosis and restenosis following angioplasty. It was reported that some heterocyclic quinone derivatives such as 6-arylamino-quinoxaline-5,8-diones and 6-arylamino-1H-benzo[d]imidazole-4,7-diones have inhibitory activity on rat aortic smooth muscle cell (RAoSMC) proliferation. To understand the structural basis for antiproliferative activity to design more potent agents, we generated pharmacophore models of representative molecules with high activity using Genetic Algorithm with Linear Assignment of Hypermolecular Alignment of Database (GALAHAD) and aligned a series of compounds to the selected pharmacophore model, then performed three-dimensional quantitative structure-activity relationship (3D-QSAR) studies using Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA). Good cross-validated correlations were obtained with CoMFA (resulting in q(2) of 0.734 and r(2) of 0.947) and CoMSIA (resulting in q(2) of 0.736 and r(2) of 0.913). The IC(50) values of the heterocyclic quinone derivatives on RAoSMC exhibited a strong correlation with steric and hydrophobic fields of the 3D structure of the molecules, resulting in the reliable prediction of inhibitory activity of the series of compounds.

Synthesis and biological evaluation of 5-arylamino-6-chloro-1H-indazole-4,7-diones as inhibitors of protein kinase B/Akt.

A series of 5-arylamino-6-chloro-1H-indazole-4,7-diones were synthesized and evaluated for their inhibitory activity on protein kinase B/Akt. The compounds exhibited a potent Akt1 inhibitory activity. Further mechanistic study revealed that they might have dual inhibitory effects on both activity and phosphorylation of Akt1 in PC-3 tumor cell line.

Synthesis and biological evaluation of 5-arylamino-1H-benzo[d]imidazole-4,7-diones as inhibitor of endothelial cell proliferation.

5-Arylamino-1H-benzo[d]imidazole-4,7-diones were synthesized and tested for their inhibitory activities on the proliferation of human umbilical vein endothelial cells (HUVECs) and the smooth muscle cells (SMCs). Among them, several 1H-benzo[d]imidazole-4,7-diones exhibited the selective antiproliferative activity on the HUVECs. Further mechanistic study revealed that the inhibitory effect of one representative 1H-benzo[d]imidazole-4,7-dione 2b on HUVEC proliferation was mediated by the activation of p38 signaling pathway in the HUVECs.

Synthesis and biological evaluation of benzimidazole-4,7-diones that inhibit vascular smooth muscle cell proliferation.

A series of 6-arylamino-5-chloro-benzimidazole-4,7-diones were synthesized and tested for their inhibitory activity on the rat aortic smooth muscle cell (RAoSMC) proliferation. Among them, 6-arylamino-5-chloro-2-methyl-benzimidazole-4,7-diones exhibited potent antiproliferative activity. Benzimidazole-4,7-dione 2c activated SAPK/JNK signaling pathway in the RAoSMCs.

Synthesis and antifungal activity of 6-arylthio-/6-arylamino-4,7-dioxobenzothiazoles.

6-Arylthio-/6-arylamino-4,7-dioxobenzothiazoles were synthesized and tested for in vitro antifungal activity against Candida species and Aspergillus niger. 6-Arylamino-4,7-dioxobenzothiazoles 5 and 6 showed, in general, more potent antifungal activity than 6-arylthio-4,7-dioxobenzothiazoles 3 and 4. The 6-arylamino-substituted compounds 5 and 6 exhibited the greatest activity. In contrast, 6-arylthio-, 2-/5-methyl- or 5-methoxy-moieties of compounds 3-4 did not improve their antifungal activity significantly. The results of this study suggest that 6-arylamino-4,7-dioxobenzothiazoles would be potent antifungal agents.

Synthesis and antifungal activity of 2,5-disubstituted-6-arylamino-4,7-benzimidazolediones.

2,5-Disubstituted-6-arylamino-4,7-benzimidazolediones were synthesized and tested for in vitro antifungal activity against pathogenic fungi. Among them, 6-arylamino-5-chloro-2-(2-pyridyl)-4,7-benzimidazolediones exhibited potent antifungal activity against Candida species and Aspergillus niger.

Synthesis and antifungal activity of 6,7-bis-[S-(aryl)thio]-5,8-quinolinediones.

6,7-Bis-[S-(aryl)thio]-5,8-quinolinediones 4 and 5 were synthesized by the substitution of 6,7-dichloro-5,8-quinolinediones with appropriate arylthiols. Their antifungal activity were tested in vitro for their growth inhibitory activities against pathogenic fungi in comparison with flucytosine. The antifungal activities were significantly improved by S-(aryl)thio moieties of the compounds 4 and 5. The all tested compounds 4 and 5 showed generally good activities against C. albicans and A. niger ranging from 0.8 to 25 microg/ml. Among them, compounds 4d-4h and 5a-5c exhibited also good activities against C. krusei and C. tropicalis. The activities of compounds 4j and 4l were comparable to those of flucytosine against all tested fungi.