Systematic study of 1,2,3-triazolyl sterols for the development of new drugs against parasitic Neglected Tropical Diseases

• Published in: European journal of medicinal chemistry Vol. 254; p. 115378
• Main Authors: Porta, Exequiel O.J., Ballari, María Sol, Carlucci, Renzo, Wilkinson, Shane, Ma, Guoyi, Tekwani, Babu L., Labadie, Guillermo R.
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 05-06-2023
• Subjects: Animals; Antiparasitic; Antiparasitic Agents - chemistry; Azasterols; Chagas Disease - drug therapy; Click chemistry; Kinetoplastid diseases; Mammals; NTDs; Parasites; Sterols - chemistry; Sterols - pharmacology; Trypanosoma cruzi; Trypanosomiasis, African - drug therapy; Azasterols; Kinetoplastid diseases; NTDs; Antiparasitic; Click chemistry
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2023.115378

A series of thirty 1,2,3-triazolylsterols, inspired by azasterols with proven antiparasitic activity, were prepared by a stereocontrolled synthesis. Ten of these compounds constitute chimeras/hybrids of 22,26-azasterol (AZA) and 1,2,3-triazolyl azasterols. The entire library was assayed against the kinetoplastid parasites Leishmania donovani, Trypanosoma cruzi, and Trypanosoma brucei, the causatives agents for visceral leishmaniasis, Chagas disease, and sleeping sickness, respectively. Most of the compounds were active at submicromolar/nanomolar concentrations with high selectivity index, when compared to their cytotoxicity against mammalian cells. Analysis of in silico physicochemical properties were conducted to rationalize the activities against the neglected tropical disease pathogens. The analogs with selective activity against L. donovani (E4, IC50 0.78 μM), T brucei (E1, IC50 0.12 μM) and T. cruzi (B1– IC50 0.33 μM), and the analogs with broad-spectrum antiparasitic activities against the three kinetoplastid parasites (B1 and B3), may be promising leads for further development as selective or broad-spectrum antiparasitic drugs.
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•A series of 1,2,3-triazolyl sterols were design and prepared.•C20 stereochemistry and sidechain substitution were modified.•All compounds were tested in T. cruzi, T. brucei, and L. donovani.•Fifteen analogs displayed submicromolar activity against one parasite.•B1 and B3 are broad-spectrum anti-kinetoplastids drugs candidates.