Design, synthesis, SAR and biological investigation of 3-(carboxymethyl)rhodanine and aminothiazole inhibitors of Mycobacterium tuberculosis Zmp1

Mattia Mori; Davide Deodato; Mohan Kasula; Davide M Ferraris; Adriana Sanna; Alessandro De Logu; Menico Rizzi; Maurizio Botta

doi:10.1016/j.bmcl.2018.01.031

Design, synthesis, SAR and biological investigation of 3-(carboxymethyl)rhodanine and aminothiazole inhibitors of Mycobacterium tuberculosis Zmp1

Bioorg Med Chem Lett. 2018 Feb 15;28(4):637-641. doi: 10.1016/j.bmcl.2018.01.031. Epub 2018 Jan 31.

Authors

Mattia Mori¹, Davide Deodato², Mohan Kasula², Davide M Ferraris³, Adriana Sanna⁴, Alessandro De Logu⁵, Menico Rizzi³, Maurizio Botta⁶

Affiliations

¹ Department of Biotechnology, Chemistry and Pharmacy, University of Siena, via Aldo Moro 2, 53019 Siena, Italy; Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, viale Regina Elena 291, 00161 Roma, Italy.
² Department of Biotechnology, Chemistry and Pharmacy, University of Siena, via Aldo Moro 2, 53019 Siena, 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 Department of Biotechnology, Chemistry and Pharmacy, University of Siena, via Aldo Moro 2, 53019 Siena, Italy; 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. Electronic address: botta@unisi.it.

PMID: 29395975
DOI: 10.1016/j.bmcl.2018.01.031

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.

Keywords: Aminothiazoles; Metalloproteases; Rhodanines; Tuberculosis; Zmp1.

MeSH terms

Antitubercular Agents / chemical synthesis
Antitubercular Agents / chemistry
Antitubercular Agents / pharmacology*
Bacterial Proteins / antagonists & inhibitors*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Metalloproteases / antagonists & inhibitors*
Microbial Sensitivity Tests
Molecular Docking Simulation
Molecular Structure
Mycobacterium tuberculosis / drug effects*
Rhodanine / chemical synthesis
Rhodanine / chemistry
Rhodanine / pharmacology*
Structure-Activity Relationship
THP-1 Cells / microbiology
Thiazoles / chemical synthesis
Thiazoles / chemistry
Thiazoles / pharmacology*

Substances

Antitubercular Agents
Bacterial Proteins
Enzyme Inhibitors
Thiazoles
Rhodanine
Metalloproteases
Zmp1 protein, Mycobacterium tuberculosis