Exploring the chemical space of 1,2,3-triazolyl triclosan analogs for discovery of new antileishmanial chemotherapeutic agents

• Published in: RSC medicinal chemistry Vol. 12; no. 1; pp. 12 - 128
• Main Authors: Fernández de Luco, Julia, Recio-Balsells, Alejandro I, Ghiano, Diego G, Bortolotti, Ana, Belardinelli, Juán Manuel, Liu, Nina, Hoffmann, Pascal, Lherbet, Christian, Tonge, Peter J, Tekwani, Babu, Morbidoni, Héctor R, Labadie, Guillermo R
• Format: Journal Article
• Language: English
• Published: Royal Society of Chemistry 01-01-2021; RSC
• Subjects: Chemical Sciences; Chemistry; Medicinal Chemistry
• ISSN: 2632-8682; 2632-8682
• DOI: 10.1039/d0md00291g

Triclosan and isoniazid are known antitubercular compounds that have proven to be also active against
Leishmania
parasites. On these grounds, a collection of 37 diverse 1,2,3-triazoles based on the antitubercular molecules triclosan and 5-octyl-2-phenoxyphenol (8PP) were designed in search of novel structures with leishmanicidal activity and prepared using different alkynes and azides. The 37 compounds were assayed against
Leishmania donovani
, the etiological agent of leishmaniasis, yielding some analogs with activity at micromolar concentrations and against
M. tuberculosis
H37Rv resulting in scarce active compounds with an MIC of 20 μM. To study the mechanism of action of these catechols, we analyzed the inhibition activity of the library on the
M. tuberculosis
enoyl-ACP reductase (ENR) InhA, obtaining poor inhibition of the enzyme. The cytotoxicity against Vero cells was also tested, resulting in none of the compounds being cytotoxic at concentrations of up to 20 μM. Derivative
5f
could be considered a valuable starting point for future antileishmanial drug development. The validation of a putative leishmanial InhA orthologue as a therapeutic target needs to be further investigated.
A collection of 37 triazolyl-triclosan derivatives were prepared as possible antileishmanial drugs. The InhA ortholog in
Leishmania donovani
was proposed as a putative druggable target.