Design,synthesis, SAR and biological investigation of 3-(carboxymethyl)rhodanine and aminothiazole inhibitors of Mycobacterium tuberculosis Zmp1 |
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| Authors: | Mattia Mori Davide Deodato Mohan Kasula Davide M Ferraris Adriana Sanna Alessandro De Logu Menico Rizzi Maurizio Botta |
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| Institution: | 1. Department of Biotechnology, Chemistry and Pharmacy, University of Siena, via Aldo Moro 2, 53019 Siena, Italy;2. Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, viale Regina Elena 291, 00161 Roma, Italy;3. DiSF-Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Via Bovio 6, 28100 Novara, Italy;4. Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Via Porcell 4, 09124 Cagliari, Italy;5. Department of Life and Enviromental Sciences, University of Cagliari, Via Porcell 4, 09124 Cagliari, Italy;6. Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, BioLife Science Bldg., Suite 333, 1900 N 12th Street, Philadelphia, PA 19122, USA |
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| Abstract: | Sixteen 3-(carboxymethyl)rhodanines, and twelve aminothiazoles as rhodanine-mimetics were designed, synthesized and tested as inhibitors of the Zmp1 enzyme from Mycobacterium tuberculosis (Mtb). Almost all rhodanines (5a–d, 5f–n, and 7a–b) exhibited Zmp1 inhibition with IC50 values in the range 1.3–43.9?µM, whereas only aminothiazoles 12b and 12d proved active with IC50 values of 41.3 and 35.7?µM, respectively. Structure-activity relationships (SAR) were coupled with molecular modeling studies to highlight structural determinants for Zmp1 inhibition. Moreover, rhodanines 5a and 5c induced 23.4 and 53.8% of Mtb growth inhibition in THP-1 infected cells, respectively, at the non-toxic concentration of 10?µg/ml. This work represents a step forward in targeting Zmp1 by small molecules. |
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| Keywords: | Rhodanines Aminothiazoles Zmp1 Tuberculosis Metalloproteases |
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