Abstract
A series of 6-substituted ureido- and thioureido-benzoxaboroles were investigated as inhibitors of carbonic anhydrases from Trypanosoma cruzi (TcCA), and Leishmania donovani chagasi (LdcCA). Both enzymes were inhibited by benzoxaboroles in the micromolar range. Preferential inhibitory potency against the β-CA LdcCA versus the α-CA TcCA was observed with submicromolar inhibitory activities. Some derivatives displayed excellent inhibitory and selectivity profile over the ubiquitous and physiological relevant human off-target hCA II. This study provides a convincing opportunity to study benzoxaborole scaffold for the design of antiprotozoan potential drugs targeting the pathogen’s carbonic anhydrases.
Highlights
Chagas disease (American trypanosomiasis) and leishmaniasis belong to the list of neglected tropical diseases developed by the World Health Organization (WHO)
Ureido and thioureido benzoxaborole 1–23 exhibited micromolar to low micromolar inhibitory activities against protozoans TcCA and LdcCA, showing a pronounced selectivity against the b-CA LdcCA with inhibition constant ranging from 3 to 0.65 lM, and selectivity ratio (KI(TcCA)/KI(LdcCA)) ranging from
We report for the first time the activity of benzoxaborole derivatives against protozoans CAs. 6-Substituted ureido and thioureido benzoxaborole derivatives 4–23 investigated here showed a preferential inhibitory activity against the b-CA from Leishmania donovani chagasi (LdcCA) versus the a-CA from TcCA
Summary
Chagas disease (American trypanosomiasis) and leishmaniasis belong to the list of neglected tropical diseases developed by the World Health Organization (WHO). Both of these diseases are caused by parasites belonging to the kinetoplastidae family and belong to the vector-borne diseases which are responsible for more than 17% of infectious diseases, affecting 20 million people and killing more than 50,000 every year[1]. Trypasonoma is transmitted by a variety of bedbugs, appeared in Latin America before spreading to other continents. Leishmania, transmitted by the bite of an infected phlebotoma, causes skin or visceral ailments that are very debilitating or even fatal if left untreated. Finding new therapeutic targets to develop new drugs is urgent for these parasitoses, which WHO classifies as priority infections (category 1: reemerging or uncontrolled infections)[2,3]
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