التفاصيل البيبلوغرافية
| العنوان: |
Aminothiazoles: Hit to lead development to identify antileishmanial agents. |
| المؤلفون: |
Bhuniya, Debnath1, Mukkavilli, Rao1, Shivahare, Rahul2, Launay, Delphine3, Dere, Ravindra T.1, Deshpande, Anil1, Verma, Aditya2, Vishwakarma, Preeti2, Moger, Manjunath1, Pradhan, Ashok1, Pati, Hari1, Gopinath, Vadiraj S.1, Gupta, Suman2 suman_gupta@cdri.res.in, Puri, Sunil K.2, Martin, Denis3 |
| المصدر: |
European Journal of Medicinal Chemistry. Sep2015, Vol. 102, p582-593. 12p. |
| مصطلحات موضوعية: |
*AMINO compounds, *THIAZOLE derivatives, *LEAD compounds, *IN vitro studies, *VISCERAL leishmaniasis, *PHARMACOKINETICS |
| مستخلص: |
As part of Drugs for Neglected Diseases initiative's lead optimization program for the development of new chemical entities to treat visceral leishmaniasis (VL), a series of aminothiazoles were synthesized and screened for in vitro efficacy, solubility and microsomal stability. The primary aim of identifying a lead structure with sub-micromolar activity was achieved. Out of 43 compounds synthesized, 16 compounds showed in vitro activity at less than 1 μM against VL. Compound 32 showed excellent antileishmanial potency (IC 50 = 3 nM) and had all the acceptable properties except for metabolic instability. Blocking the metabolic soft spots in compound 32 , where the 4-methoxy pyridine substituent was replaced by 5-ethoxy group, led to compound 36 (IC 50 = 280 nM) with improved stability. To understand the disposition of 36 , in vivo pharmacokinetic study was conducted in a mouse model. Compound 36 showed high clearance (91 mL/min/kg); short half-life (0.48 h) after intravenous administration (1 mg/kg) and exposure (AUC 0-24 ) following oral administration was 362 ng h/mL with absolute bioavailability of 8%. To summarize, 43 analogs were synthesized out of which 15 compounds showed very potent sub-nanomolar efficacy in in vitro systems but the liability of metabolic instability seemed to be the major challenge for this chemical class and remains to be addressed. [ABSTRACT FROM AUTHOR] |
| قاعدة البيانات: |
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