Appraisal of anti-protozoan activity of nitroaromatic benzenesulfonamides inhibiting carbonic anhydrases fromTrypanosoma cruziandLeishmania donovani

Abstract

Chagas disease and leishmaniasis are neglected tropical disorders caused by the protozoans Trypanosoma cruzi and Leishmania spp. Carbonic anhydrases (CAs, EC 4.2.1.1) from these protozoans (α-TcCA and β-LdcCA) have been validated as promising targets for chemotherapic interventions. Many anti-protozoan agents, such as nitroimidazoles, nifurtimox, and benznidazole possess a nitro aromatic group in their structure which is crucial for their activity. As a continuation of our previous work on N -nitrosulfonamides as anti-protozoan agents, we investigated benzenesulfonamides bearing a nitro aromatic moiety against TcCA and LdcCA, observing selective inhibitions over human off-target CAs. Selected derivatives were assessed in vitro in different developmental stages of T. cruzi and Leishmania spp. A lack of significant growth inhibition has been found, which has been connected to the low permeability of this class of derivatives through cell membranes. Further strategies necessarily need to be designed for targeting Chagas disease and leishmaniasis with nitro-containing CA inhibitors.

Coumarin carbonic anhydrase inhibitors from natural sources

“…Overall, the very interesting moieties present in the NP coumarins make them a source of inspiration for medicinal chemists and pharmacologists in the search of new drugs with a safer profile and specific action in a variety of disorders, starting from the infective ones 79 and ending with tumours 80 and inflammatory diseases 81 . For the moment, only the human a-CAs were investigated for their inhibition profile with coumarins, but such enzymes are also present in other organisms, such as pathogenic bacteria, protozoans, and fungi [82][83][84][85] . Investigation of coumarin derivatives (including NPCs) against these enzymes may thus lead to interesting developments in the fight of infections produced by such pathogens.…”

Drug repurposing for Chagas disease: In vitro assessment of nimesulide against Trypanosoma cruzi and insights on its mechanisms of action

“…nifurtimox which has severe limitations mainly in the chronic phase of the infection [28]. Several compounds were tested in order to identify their activity, including those from the class of nitroaromatics [29]. Indeed, interest in molecules containing the nitro group has undergone a resurgence in recent years, due to a greater understanding of the role of nitro-reductases involved in their activation and also on the mechanisms by which parasites develop resistance [30].…”

Mycobacterium tuberculosis β-Carbonic Anhydrases: Novel Targets for Developing Antituberculosis Drugs

“…In the recent past, CAs belonging to the β -CA family have emerged as potential targets for developing drugs against diseases caused by bacterial and parasitic pathogens. Indeed, several in vitro inhibition studies have shown that the β -CAs from pathogenic bacteria and parasitic pathogens can be inhibited by certain compounds [12,13,14,15,16,17,18,19,20,21,22,23,24]. Among these inhibitors are sulfonamides and their bioisosteres, which are the main classes of CA inhibitors that have been in clinical use for more than 50 years [25,26,27,28].…”