22625-57-6Relevant articles and documents
Aluminium-Catalysed Oxazolidinone Synthesis and their Conversion into Functional Non-Symmetrical Ureas
Laserna, Victor,Guo, Wusheng,Kleij, Arjan W.
, p. 2849 - 2854 (2015/09/28)
An efficient and practical aluminium-catalysed approach towards a range of functional oxazolidinones is reported. The method is based on cheap and readily available starting materials including terminal and internal (bicyclic) epoxides and phenyl carbamate. The oxazolidinones serve as highly useful synthons for the high yield preparation of non-symmetrical ureas by nucleophilic ring-opening affording the targeted urea compounds with excellent functional group diversity, high regioselectivity and isolated yields up to >99%.
Methyl-thiazoles: A novel mode of inhibition with the potential to develop novel inhibitors targeting InhA in mycobacterium tuberculosis
Shirude, Pravin S.,Madhavapeddi, Prashanti,Naik, Maruti,Murugan, Kannan,Shinde, Vikas,Nandishaiah, Radha,Bhat, Jyothi,Kumar, Anupriya,Hameed, Shahul,Holdgate, Geoffrey,Davies, Gareth,McMiken, Helen,Hegde, Naina,Ambady, Anisha,Venkatraman, Janani,Panda, Manoranjan,Bandodkar, Balachandra,Sambandamurthy, Vasan K.,Read, Jon A.
, p. 8533 - 8542 (2013/12/04)
InhA is a well validated Mycobacterium tuberculosis (Mtb) target as evidenced by the clinical success of isoniazid. Translating enzyme inhibition to bacterial cidality by targeting the fatty acid substrate site of InhA remains a daunting challenge. The recent disclosure of a methyl-thiazole series demonstrates that bacterial cidality can be achieved with potent enzyme inhibition and appropriate physicochemical properties. In this study, we report the molecular mode of action of a lead methyl-thiazole, along with analogues with improved CYP inhibition profile. We have identified a novel mechanism of InhA inhibition characterized by a hitherto unreported "Y158-out" inhibitor-bound conformation of the protein that accommodates a neutrally charged "warhead". An additional novel hydrophilic interaction with protein residue M98 allows the incorporation of favorable physicochemical properties for cellular activity. Notably, the methyl-thiazole prefers the NADH-bound form of the enzyme with a Kd of ～13.7 nM, as against the NAD+-bound form of the enzyme.
2-(4-Carbonylphenyl)benzoxazole inhibitors of CETP: Attenuation of hERG binding and improved HDLc-raising efficacy
Sweis, Ramzi F.,Hunt, Julianne A.,Sinclair, Peter J.,Chen, Ying,Eveland, Suzanne S.,Guo, Qiu,Hyland, Sheryl A.,Milot, Denise P.,Cumiskey, Anne-Marie,Latham, Melanie,Rosa, Raymond,Peterson, Larry,Sparrow, Carl P.,Anderson, Matt S.
scheme or table, p. 2597 - 2600 (2011/06/20)
The development of 2-phenylbenzoxazoles as inhibitors of cholesteryl ester transfer protein (CETP) is described. Efforts focused on finding suitable replacements for the central piperidine with the aim of reducing hERG binding: a main liability of our benchmark benzoxazole (1a). Replacement of the piperidine with a cyclohexyl group successfully attenuated hERG binding, but was accompanied by reduced in vivo efficacy. The approach of substituting a piperidine moiety with an oxazolidinone also attenuated hERG binding. Further refinement of this latter scaffold via SAR at the pyridine terminus and methyl branching on the oxazolidinone led to compounds 7e and 7f, which raised HDLc by 33 and 27 mg/dl, respectively, in our transgenic mouse PD model and without the hERG liability of previous series.
