Scaffold Morphing To Identify Novel DprE1 Inhibitors with Antimycobacterial Activity

被引：33

作者：

Manjunatha, M. R. ^{[1
]}

Shandil, Radha ^{[2
,8
]}

Panda, Manoranjan ^{[1
]}

Sadler, Claire ^{[3
]}

Ambady, Anisha ^{[4
]}

Panduga, Vijender ^{[2
]}

Kumar, Naveen ^{[2
]}

Mahadevaswamy, Jyothi ^{[4
]}

Sreenivasaiah, M. ^{[1
]}

Narayan, Ashwini ^{[4
]}

Guptha, Supreeth ^{[4
]}

Sharma, Sreevalli ^{[4
]}

Sambandamurthy, Vasan K. ^{[4
]}

Ramachandran, Vasanthi ^{[4
]}

Mallya, Meenakshi ^{[1
]}

Cooper, Christopher ^{[5
]}

Mdluli, Khisi ^{[5
]}

Butler, Scott ^{[6
]}

Tommasi, Ruben ^{[6
]}

Iyer, Pravin S. ^{[1
]}

Narayanan, Shridhar ^{[4
,8
]}

Chatterji, Monalisa ^{[4
]}

Shirude, Pravin S. ^{[1
,7
]}

机构：

[1] AstraZeneca India, Dept Med Chem, IMED Infect, Bellary Rd, Bangalore 560024, Karnataka, India

[2] AstraZeneca, DMPK & Anim Sci, IMED Infect, Bangalore 560024, Karnataka, India

[3] AstraZeneca, Safety Assessment, IMED, Alderly Pk, Mereside, England

[4] AstraZeneca, IMED Infect, Dept Biosci, Bangalore 560024, Karnataka, India

[5] Global Alliance TB, New York, NY 10005 USA

[6] AstraZeneca, GHP, Infect IMED, Waltham, MA 02451 USA

[7] Biocon Bristol Myers Squibb Res & Dev Ctr, Bommasandra Jigani Link Rd, Bangalore 560099, Karnataka, India

[8] Fdn Neglected Dis Res, 20A KIADB Ind Area, Bengaluru 561203, India

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2019年 / 10卷 / 10期

关键词：

DprE1; Mycobacterium tuberculosis; azaindole; benzimidazole; KILL MYCOBACTERIUM-TUBERCULOSIS; ARABINAN; MODEL;

D O I：

10.1021/acsmedchemlett.9b00343

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We report a novel benzimidazole (BI) based DprE1 inhibitor that resulted from scaffold morphing of a 1,4-azaindole series. The clinical progression of the 1,4-azaindole series from our previous work validates the potential of exploring newer chemical entities with antimycobacterial activity driven via a noncovalent inhibition of the decaprenylphosphoryl-beta-D-ribose-2'-epimerase (DprE1). The representative compounds from the new scaffold reported in this study exhibited an improved solubility and higher free plasma fraction, while retaining potent DprE1 inhibition and antimycobacterial activity. A representative compound from the benzimidazole series demonstrated good efficacy in a murine model of tuberculosis. Furthermore, molecular modeling of the BI scaffold suggests plausible modes of binding in the active site of DprE1 enzyme from Mycobacterium tuberculosis that can be used for further exploration of the series.

引用

页码：1480 / 1485

页数：11

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