AUTHOR=Gonzaga Daniel T. G. , Oliveira Felipe H. , Ranke N. L. von , Pinho G. Q. , Salles Juliana P. , Bello Murilo L. , Rodrigues Carlos R. , Castro Helena C. , Souza Hellen V. C. M. de , Reis Caroline R. C. , Leme Rennan P. P. , Mafra João C. M. , Pinheiro Luiz C. S. , Hoelz Lucas V. B. , Boechat Nubia , Faria Robson X. 

TITLE=Synthesis, Biological Evaluation, and Molecular Modeling Studies of New Thiadiazole Derivatives as Potent P2X7 Receptor Inhibitors

JOURNAL=Frontiers in Chemistry

VOLUME=7

YEAR=2019

URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2019.00261

DOI=10.3389/fchem.2019.00261

ISSN=2296-2646

ABSTRACT=<p>Twenty new 2-(1<italic>H</italic>-pyrazol-1-yl)-1,3,4-thiadiazole analogs were synthetized to develop P2X7 receptor (P2X7R) inhibitors. P2X7R inhibition <italic>in vitro</italic> was evaluated in mouse peritoneal macrophages, HEK-293 cells transfected with hP2X7R (dye uptake assay), and THP-1 cells (IL-1β release assay). The 1-(5-phenyl-1,3,4-thiadiazol-2-yl)-1<italic>H</italic>-pyrazol-5-amine derivatives <bold>9b</bold>, <bold>9c</bold>, and <bold>9f</bold>, and 2-(3,5-dimethyl-1<italic>H</italic>-pyrazol-1-yl)-5-(4-fluorophenyl)-1,3,4-thiadiazole (<bold>11c</bold>) showed inhibitory effects with IC<sub>50</sub> values ranging from 16 to 122 nM for reduced P2X7R-mediated dye uptake and 20 to 300 nM for IL-1β release. In addition, the <italic>in vitro</italic> ADMET profile of the four most potent derivatives was determined to be in acceptable ranges concerning metabolic stability and cytotoxicity. Molecular docking and molecular dynamics simulation studies of the molecular complexes human P2X7R/<bold>9f</bold> and murine P2X7R/<bold>9f</bold> indicated the putative intermolecular interactions. Compound <bold>9f</bold> showed affinity mainly for the Arg268, Lys377, and Asn266 residues. These results suggest that 2-(1<italic>H</italic>-pyrazol-1-yl)-1,3,4-thiadiazole analogs may be promising novel P2X7R inhibitors with therapeutic potential.</p>