Triclosan-caffeic acid hybrids: Synthesis, leishmanicidal, trypanocidal and cytotoxic activities

• Published in: European journal of medicinal chemistry 2017-12, Vol.141, p.73-83
• Main Authors: Otero, Elver, García, Elisa, Palacios, Genesis, Yepes, Lina M., Carda, Miguel, Agut, Raúl, Vélez, Iván D., Cardona, Wilson I., Robledo, Sara M.
• Format: Article
• Language: English
• Subjects: Antiprotozoal activity; Antiprotozoal Agents - chemical synthesis; Antiprotozoal Agents - chemistry; Antiprotozoal Agents - pharmacology; Caffeic acid; Caffeic Acids - chemical synthesis; Caffeic Acids - chemistry; Caffeic Acids - pharmacology; Cell Line; Cell Survival - drug effects; Chagas disease; Cytotoxicity; Dose-Response Relationship, Drug; Humans; Hybrids; Leishmania - drug effects; Leishmaniasis; Macrophages - drug effects; Molecular Structure; Parasitic Sensitivity Tests; Structure-Activity Relationship; Triclosan; Triclosan - chemical synthesis; Triclosan - chemistry; Triclosan - pharmacology; Trypanosoma cruzi; Trypanosoma cruzi - drug effects
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2017.09.064

The synthesis, cytotoxicity, anti-leishmanial and anti-trypanosomal activities of twelve triclosan-caffeic acid hybrids are described herein. The structure of the synthesized products was elucidated by a combination of spectrometric analyses. The synthesized compounds were evaluated against amastigotes forms of L. (V) panamensis, which is the most prevalent Leishmania species in Colombia, and against Trypanosoma cruzi, which is the pathogenic species to humans. Cytotoxicity was evaluated against human U-937 macrophages. Eight compounds were active against L. (V) panamensis (18–23, 26 and 30) and eight of them against T. cruzi (19–22, 24 and 28–30) with EC50 values lower than 40 μM. Compounds 19–22, 24 and 28–30 showed higher activities than benznidazole (BNZ). Esters 19 and 21 were the most active compounds for both L. (V) panamensis and T. cruzi with 3.82 and 11.65 μM and 8.25 and 8.69 μM, respectively. Compounds 19–22, 24 and 28–30 showed higher activities than benznidazole (BNZ). Most of the compounds showed antiprotozoal activity and with exception of 18, 26 and 28, the remaining compounds were toxic for mammalian cells, yet they have potential to be considered as candidates for anti-trypanosomal and anti-leishmanial drug development. The activity is dependent on the length of the alkyl linker with compound 19, bearing a four-carbon alkyl chain, the most performing hybrid. In general, hydroxyl groups increase both activity and cytotoxicity and the presence of the double bond in the side chain is not decisive for cytotoxicity and anti-protozoal activity. [Display omitted] •Twelve triclosan-caffeic acid hybrids were synthesized.•Eight hybrids were active against L. (V) panamensis and eight against T. cruzi.•Higher bioactivity is achieved when the alkyl linker has four and seven carbon atoms.•Hydroxyl groups of caffeic moiety increase both activity and cytotoxicity.•Double bond is not decisive for cytotoxicity and anti-leishmanial activity.