Potent naphthoquinones against antimony-sensitive and -resistant Leishmania parasites: Synthesis of novel α- and nor-α-lapachone-based 1,2,3-triazoles by copper-catalyzed azide–alkyne cycloaddition

• Published in: European journal of medicinal chemistry Vol. 63; pp. 523 - 530
• Main Authors: Guimarães, Tiago T., Pinto, Maria do Carmo F.R., Lanza, Juliane S., Melo, Maria N., do Monte-Neto, Rubens L., de Melo, Isadora M.M., Diogo, Emilay B.T., Ferreira, Vitor F., Camara, Celso A., Valença, Wagner O., de Oliveira, Ronaldo N., Frézard, Frédéric, da Silva Júnior, Eufrânio N.
• Format: Journal Article
• Language: English
• Published: PARIS Elsevier Masson SAS 01.05.2013; Elsevier
• Subjects: Alkynes - chemistry; Animals; Antimony - pharmacology; Antiprotozoal Agents - chemical synthesis; Antiprotozoal Agents - chemistry; Antiprotozoal Agents - pharmacology; Azides - chemistry; Catalysis; Cell Survival - drug effects; Cells, Cultured; Chemistry, Medicinal; Chemotherapy; Click chemistry; Copper - chemistry; Cycloaddition Reaction - methods; Drug Resistance - drug effects; Lapachone; Leishmania; Leishmania - drug effects; Leishmania infantum - drug effects; Life Sciences & Biomedicine; Macrophages, Peritoneal - cytology; Macrophages, Peritoneal - drug effects; Mice; Naphthoquinones - chemical synthesis; Naphthoquinones - chemistry; Naphthoquinones - pharmacology; Parasitic Sensitivity Tests; Pharmacology & Pharmacy; Quinones; Science & Technology; Species Specificity; Triazoles - chemical synthesis; Triazoles - chemistry; Triazoles - pharmacology; Quinones; Chemotherapy; Click chemistry; Lapachone; Leishmania; TERMINAL ALKYNES; DRUG-RESISTANCE; AMPHOTERICIN-B; BETA-LAPACHONE; TRYPANOSOMA-CRUZI ACTIVITY; PERSPECTIVES; MILTEFOSINE; AMAZONENSIS; VISCERAL LEISHMANIASIS; DERIVATIVES
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2013.02.038

Continuing our screening program for novel anti-parasite compounds, we synthesized seven 1,4-naphthoquinones coupled to 1,2,3-triazoles, five nor-β-lapachone-based 1,2,3-triazoles and ten α-lapachone-based 1,2,3-triazoles. These and other naphthoquinonoid compounds were evaluated for their activity against promastigote forms of antimony-sensitive and -resistant strains of Leishmania infantum (syn. Leishmania chagasi) and Leishmania amazonensis. The toxicity of these compounds to mammalian cells was also examined. The substances were more potent than an antimonial drug, with IC50 values ranging from 1.0 to 50.7 μM. Nor-α-lapachone derivatives showed the highest antileishmanial activity, with selectivity indices in the range of 10–15. These compounds emerged as important leads for further investigation as antileishmanial agents. Additionally, one of these compounds exhibited cross-resistance in Sb-resistant Leishmania and could provide a molecular tool for investigating the multidrug resistance mechanisms in Leishmania parasites. [Display omitted] ► Lapachones were obtained with leishmanicidal activity. ► α-Lapachone-based 1,2,3-triazoles active against Leishmania parasites were developed. ► Potent quinones against Leishmania were prepared with high selectivity indices.