Benzisothiazolinone as a useful template for the design of new monoacylglycerol lipase inhibitors : investigation of the target residues and comparison with octhilinone

The regulation of 2-arachidonoylglycerol (2-AG) levels is a major issue as 2-AG has been proven to participate in numerous physiopathological phenomena such as neuroprotection or analgesia. Octhilinone, a cysteine-reagent compound, has recently been shown to inhibit in the nanomolar range monoacylglycerol lipase (MAGL), the major enzyme responsible for the degradation of 2-AG. Here, we further investigate the mechanism by which octhilinone and its benzisothiazolinone analog inhibit human MAGL. We also provide new information on the structural requirements for MAGL inhibition by these compounds. Finally, we describe for N-octylbenzisothiazolinone a mode of inhibition which is partially different from that described for octhilinone, especially with regard to the targeted cysteine residues in the vicinity of the catalytic site

Pharmacomodulations of the benzoyl-thiosemicarbazide scaffold reveal antimicrobial agents targeting D-alanyl-D-alanine ligase in bacterio

D-Alanyl-D-alanine ligase (Ddl) is a validated and attractive target among the bacterial enzymes involved in peptidoglycan biosynthesis. In the present work, we investigated the pharmacomodulations of the benzoylthiosemicarbazide scaffold to identify new Ddl inhibitors with antibacterial potency. Five novel series of thiosemicarbazide analogues, 1,2,4-thiotriazole-3-thiones, 1,3,4-thiadiazoles, phenylthiosemicarbazones, diacylthiosemicarbazides and thioureas were synthesized via straightforward procedures, then tested against Ddl and on susceptible or resistant bacterial strains. Among these, the thiosemicarbazone and thiotriazole were identified as the most promising scaffolds with Ddl inhibition potency in the micromolar range. Antimicrobial evaluation of salicylaldehyde-4(N)-(3,4-dichlorophenyl) thiosemicarbazone 33, one of the best compounds in our study, revealed interesting antimicrobial activities with values of 3.12 to 6.25 µM (1.06-2.12 µg/mL) against VRE strains and 12.5-25.0 µM (4.25-8.50 µg/mL) towards MRSA and VRSA strains. A detailed mechanistic study was conducted on the Ddl inhibitors 4-(3,4-dichlorophenyl)-5-(2-hydroxyphenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione 20 and compound 33, and revealed a bactericidal effect at 5xMIC concentration after 7h and 24h, respectively, and a bacteriostatic effect at 1×MIC or 2×MIC without any sign of bacterial membrane disruption at these lower concentrations. Finally, 20 and 33 were proved to target Ddl in bacterio via intracellular LC-MS dosage of D-Ala, L-Ala and D-Ala-D-Ala. Although, at this stage, our results indicate that other mechanisms might be involved to explain the antimicrobial potency of our compounds, their ability to inhibit the growth of strains resistant to usual antibiotics, as well as strains that express alternative ligases, sets the stage for the development of new antimicrobial agents potentially less sensitive to resistance mechanisms

Convenient one-pot formation of highly functionalized 5-bromo-2-aminothiazoles, potential endocannabinoid hydrolase MAGL inhibitors

Highly functionalized 5-bromo-2-amino-1,3-thiazoles bearing various substituents could be easily prepared by a rapid and efficient one-pot method, using simple starting materials and mild conditions while avoiding the use of metal catalysts or inconvenient reagents such as elemental halogens. These useful products can serve as starting materials for other reactions or as pharmacologically interesting compounds. In our work we have shown that the resulting 5-bromothiazole compounds could lead to monoacylglycerol lipase (MAGL) inhibition in the lM range

CCDC 1980940: Experimental Crystal Structure Determination

Related Article: Alice Ameryckx, Lionel Pochet, Gang Wang, Esra Yildiz, Bouazza Es Saadi, Johan Wouters, Françoise Van Bambeke, Raphaël Frédérick|2020|Eur.J.Med.Chem.|200|112444|doi:10.1016/j.ejmech.2020.11244

CCDC 1851262: Experimental Crystal Structure Determination

Related Article: Julien R.C. Prevost, Arina Kozlova, Bouazza Es Saadi, Esra Yildiz, Sara Modaffari, Didier M. Lambert, Lionel Pochet, Johan Wouters, Eduard Dolušić, Raphaël Frédérick|2018|Tetrahedron Lett.|59|4315|doi:10.1016/j.tetlet.2018.10.055,An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

CCDC 1851263: Experimental Crystal Structure Determination

Related Article: Julien R.C. Prevost, Arina Kozlova, Bouazza Es Saadi, Esra Yildiz, Sara Modaffari, Didier M. Lambert, Lionel Pochet, Johan Wouters, Eduard Dolušić, Raphaël Frédérick|2018|Tetrahedron Lett.|59|4315|doi:10.1016/j.tetlet.2018.10.055,An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

CCDC 1980941: Experimental Crystal Structure Determination

Related Article: Alice Ameryckx, Lionel Pochet, Gang Wang, Esra Yildiz, Bouazza Es Saadi, Johan Wouters, Françoise Van Bambeke, Raphaël Frédérick|2020|Eur.J.Med.Chem.|200|112444|doi:10.1016/j.ejmech.2020.11244