Fluorovinylsulfones and -Sulfonates as Potent Covalent Reversible Inhibitors of the Trypanosomal Cysteine Protease Rhodesain: Structure-Activity Relationship, Inhibition Mechanism, Metabolism, and In Vivo Studies was written by Jung, Sascha;Fuchs, Natalie;Johe, Patrick;Wagner, Annika;Diehl, Erika;Yuliani, Tri;Zimmer, Collin;Barthels, Fabian;Zimmermann, Robert A.;Klein, Philipp;Waigel, Waldemar;Meyr, Jessica;Opatz, Till;Tenzer, Stefan;Distler, Ute;Raeder, Hans-Joachim;Kersten, Christian;Engels, Bernd;Hellmich, Ute A.;Klein, Jochen;Schirmeister, Tanja. And the article was included in Journal of Medicinal Chemistry in 2021.Category: chlorides-buliding-blocks This article mentions the following:
Rhodesain is a major cysteine protease of Trypanosoma brucei rhodesiense, a pathogen causing Human African Trypanosomiasis, and a validated drug target. Recently, we reported the development of α-halovinylsulfones as a new class of covalent reversible cysteine protease inhibitors. Here, α-fluorovinylsulfones/-sulfonates were optimized for rhodesain based on mol. modeling approaches. I (X = F), the most potent and selective inhibitor in the series, shows a single-digit nanomolar affinity and high selectivity toward mammalian cathepsins B and L. Enzymic dilution assays and MS experiments indicate that I (X = F) is a slow-tight binder (Ki = 3 nM). Furthermore, the nonfluorinated I (X = H) shows favorable metabolism and biodistribution by accumulation in mice brain tissue after i.p. and oral administration. The highest antitrypanosomal activity was observed for inhibitors with an N-terminal 2,3-dihydrobenzo[b][1,4]dioxine group and a 4-Me-Phe residue in P2 with nanomolar EC50 values (0.14/0.80μM). The different mechanisms of reversible and irreversible inhibitors were explained using QM/MM calculations and MD simulations. In the experiment, the researchers used many compounds, for example, (Chloromethanetriyl)tribenzene (cas: 76-83-5Category: chlorides-buliding-blocks).
(Chloromethanetriyl)tribenzene (cas: 76-83-5) belongs to organic chlorides. Chlorination modifies the physical properties of hydrocarbons in several ways. These compounds are typically denser than water due to the higher atomic weight of chlorine versus hydrogen. Aryl chlorides may be prepared by the Friedel-Crafts halogenation, using chlorine and a Lewis acid catalyst.Category: chlorides-buliding-blocks
Referemce:
Chloride – Wikipedia,
Chlorides – an overview | ScienceDirect Topics