Journal ArticleDOI
Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis
Kevin Pethe,Pablo Bifani,Jichan Jang,Sunhee Kang,Seijin Park,Sujin Ahn,Jan Jiricek,Ju-Young Jung,Hee Kyoung Jeon,Jonathan Cechetto,Thierry Christophe,Honggun Lee,Marie Kempf,Mary Jackson,Anne J. Lenaerts,Hang Ohuong Pham,Victoria Jones,Min Jung Seo,Young-Mi Kim,Mooyoung Seo,Jeong Jea Seo,Dongsik Park,Yoonae Ko,Inhee Choi,Ryangyeo Kim,Se Yeon Kim,Seungbin Lim,Seung-Ae Yim,Jiyoun Nam,Hwankyu Kang,Haejin Kwon,Chun-Taek Oh,Yoojin Cho,Yunhee Jang,Junghwan Kim,Adeline C. Y. Chua,Bee Huat Tan,Mahesh Nanjundappa,Srinivasa P. S. Rao,Whitney Barnes,René Wintjens,John R. Walker,Sylvie Alonso,Saeyeon Lee,Jungjun Kim,Soohyun Oh,Taegwon Oh,Ulf Nehrbass,Sung-Jun Han,Zaesung No,Jinhwa Lee,Priscille Brodin,Sang Nae Cho,Kiyean Nam,Jaeseung Kim +54 more
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TLDR
The optimized IPA compound Q203 inhibited the growth of MDR and XDR M. tuberculosis clinical isolates in culture broth medium in the low nanomolar range and was efficacious in a mouse model of tuberculosis at a dose less than 1 mg per kg body weight, which highlights the potency of this compound.Abstract:
New therapeutic strategies are needed to combat the tuberculosis pandemic and the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) forms of the disease, which remain a serious public health challenge worldwide. The most urgent clinical need is to discover potent agents capable of reducing the duration of MDR and XDR tuberculosis therapy with a success rate comparable to that of current therapies for drug-susceptible tuberculosis. The last decade has seen the discovery of new agent classes for the management of tuberculosis, several of which are currently in clinical trials. However, given the high attrition rate of drug candidates during clinical development and the emergence of drug resistance, the discovery of additional clinical candidates is clearly needed. Here, we report on a promising class of imidazopyridine amide (IPA) compounds that block Mycobacterium tuberculosis growth by targeting the respiratory cytochrome bc1 complex. The optimized IPA compound Q203 inhibited the growth of MDR and XDR M. tuberculosis clinical isolates in culture broth medium in the low nanomolar range and was efficacious in a mouse model of tuberculosis at a dose less than 1 mg per kg body weight, which highlights the potency of this compound. In addition, Q203 displays pharmacokinetic and safety profiles compatible with once-daily dosing. Together, our data indicate that Q203 is a promising new clinical candidate for the treatment of tuberculosis.read more
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Pyrazolo[1,5- a]pyridine Inhibitor of the Respiratory Cytochrome bcc Complex for the Treatment of Drug-Resistant Tuberculosis
Xiaoyun Lu,Zoe C. Williams,Kiel Hards,Kiel Hards,Jian Tang,Jian Tang,Chen-Yi Cheung,Htin Lin Aung,Htin Lin Aung,Bangxing Wang,Bangxing Wang,Zhiyong Liu,Zhiyong Liu,Xianglong Hu,Anne J. Lenaerts,Lisa K. Woolhiser,Courtney Hastings,Xiantao Zhang,Zhe Wang,Kyu Y. Rhee,Ke Ding,Tianyu Zhang,Tianyu Zhang,Gregory M. Cook,Gregory M. Cook +24 more
TL;DR: It is proposed that TB47 is an effective lead compound for the development of novel tuberculosis chemotherapies, suggesting a promising role in combination therapies.
Journal ArticleDOI
Decarboxylative Negishi Coupling of Redox-Active Aliphatic Esters by Cobalt Catalysis.
TL;DR: A cobalt-catalyzed decarboxylative Negishi coupling reaction of redox-active aliphatic esters with organozinc reagents was developed and Mechanistic studies indicated that a radical mechanism is involved.
Journal ArticleDOI
Hit Generation in TB Drug Discovery: From Genome to Granuloma
TL;DR: This review describes efforts using surrogates and engineered strains of Mtb to focus screens on specific targets, and assesses different models, their ability to generate hit compounds, and needs for further TB drug development, to provide direction for future TB drug discovery.
Journal ArticleDOI
Visible-Light Photocatalysis as an Enabling Tool for the Functionalization of Unactivated C(sp3)-Substrates
Sara Roslin,Luke R. Odell +1 more
TL;DR: In this paper, the authors summarize the recent developments in the use of visible-light photocatalysis for the functionalization of unactivated C(sp3)-substrates.
Journal ArticleDOI
Drug resistance mechanisms and novel drug targets for tuberculosis therapy
Mahmudul Islam,H.M. Adnan Hameed,Julius Mugweru,Chiranjibi Chhotaray,Changwei Wang,Yaoju Tan,Jianxiong Liu,Xinjie Li,Shouyong Tan,Iwao Ojima,Wing Wai Yew,Eric L. Nuermberger,Gyanu Lamichhane,Tianyu Zhang,Tianyu Zhang +14 more
TL;DR: The anti-TB drug resistance mechanisms are summarized, some possible novel drug targets in the development of new agents for TB therapy are furnished, and the usefulness using known targets to develop new anti- TB drugs is discussed.
References
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Koen Andries,Peter Verhasselt,Jerome Guillemont,Hinrich W. H. Göhlmann,Jean-Marc Neefs,Hans Winkler,Jef Van Gestel,Philip Timmerman,Min Zhu,Ennis Lee,Peter Williams,Didier de Chaffoy,Emma Huitric,Sven Hoffner,Emmanuelle Cambau,Chantal Truffot-Pernot,Nacer Lounis,Vincent Jarlier +17 more
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Journal ArticleDOI
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C. Kendall Stover,Paul Warrener,Donald R. VanDevanter,David R. Sherman,Taraq M. Arain,Michael H. Langhorne,Scott Anderson,J. Andrew Towell,Ying Yuan,David N. McMurray,Barry N. Kreiswirth,Clifton E. Barry,William R. Baker +12 more
TL;DR: It is concluded that nitroimidazopyrans offer the practical qualities of a small molecule with the potential for the treatment of tuberculosis and bactericidal activity against both replicating and static M. tuberculosis.
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