3351-92-6Relevant articles and documents
Targeting mycobacterium protein tyrosine phosphatase B for antituberculosis agents
Zhou, Bo,He, Yantao,Zhang, Xian,Xu, Jie,Luo, Yong,Wang, Yuehong,Franzblau, Scott G.,Yang, Zhenyun,Chan, Rebecca J.,Liu, Yan,Zheng, Jianyu,Zhang, Zhong-Yin
scheme or table, p. 4573 - 4578 (2010/10/03)
Protein tyrosine phosphatases are often exploited and subverted by pathogenic bacteria to cause human diseases. The tyrosine phosphatase mPTPB from Mycobacterium tuberculosis is an essential virulence factor that is secreted by the bacterium into the cytoplasm of macrophages, where it mediates mycobacterial survival in the host. Consequently, there is considerable interest in understanding the mechanism by which mPTPB evades the host immune responses, and in developing potent and selective mPTPB inhibitors as unique antituberculosis (antiTB) agents. We uncovered that mPTPB subverts the innate immune responses by blocking the ERK1/2 and p38 mediated IL-6 production and promoting host cell survival by activating the Akt pathway. We identified a potent and selective mPTPB inhibitor I-A09 with highly efficacious cellular activity, from a combinatorial library of bidentate benzofuran salicylic acid derivatives assembled by click chemistry. We demonstrated that inhibition of mPTPB with I-A09 in macrophages reverses the altered host immune responses induced by the bacterial phosphatase and prevents TB growth in host cells. The results provide the necessary proof-of-principle data to support the notion that specific inhibitors of the mPTPB may serve as effective antiTB therapeutics.
Novel 5-hydroxytryptamine (5-HT3) receptor antagonists. I. Synthesis and structure-activity relationships of conformationally restricted fused imidazole derivatives
Ohta, Mitsuaki,Suzuki, Takeshi,Koide, Tokuo,Matsuhisa, Akira,Furuya, Toshio,Miyata, Keiji,Yanagisawa, Isao
, p. 991 - 999 (2007/10/03)
We prepared a novel series of conformationally restricted fused imidazole derivatives 4b, 4c and 4d (possessing 4,5,6,7-tetrahydroimidazo[4,5- c]pyridine and substituted 4,5,6,7-tetrahydro-1H-benzimidazole for 4b, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine for 4c and 5,6,7,8- tetrahydroimidazo[1,5-a]pyridine for 4d as a basic amine part and (2- methoxyphenyl)aminocarbonyl group as an aromatic-carbonyl part). Their activities were then evaluated as an 5-hydroxytryptamine (5-HT3) receptor antagonist which may be useful for the treatment of irritable bowel syndrome (IBS) as well as for nausea and vomiting associated with cancer chemotherapy. The most potent compound was N-(2-methoxyphenyl)-4,5,6,7-tetrahydro-1H- benzimidazole-5-carboxamide 14 in this series with an ID50 value of 0.32 μg/kg on the von Bezold-Jarisch reflex in rats and an IC50 value of 0.43 μM on the isolated colonic contraction in guinea pig, approximately ten and two times more potent than ondansetron 1, respectively. The structure- activity relationships (SAR) study suggested that the high potency of 14 may be attributed to the suitable position and direction of the N-C-N centroid in the conformationally restricted imidazole ring against the planar (2-methoxy- phenyl)aminocarbonyl part in the binding of 14 to the receptor.
