Synthesis, Cytotoxicity and In Vitro Antileishmanial Activity of Naphthothiazoles

• Published in: Chemical biology & drug design 2013-06, Vol.81 (6), p.749-756
• Main Authors: de Toledo, Juliano S., Junior, Paulo E. S., Manfrim, Viviane, Pinzan, Camila F., de Araujo, Alexandre S., Cruz, Angela K., Emery, Flavio S.
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Antiprotozoal Agents - chemical synthesis; Antiprotozoal Agents - pharmacokinetics; Antiprotozoal Agents - toxicity; Biological Availability; Blood Proteins - metabolism; Cell Survival - drug effects; fragment embedment; Half-Life; Humans; Leishmania braziliensis; Leishmania braziliensis - drug effects; leishmaniasis; Macrophages - cytology; Mice; Mice, Inbred BALB C; naphthothiazoles; neglected tropical disease; Protein Binding; Thiazoles - chemistry; Thiazoles - pharmacokinetics; Thiazoles - toxicity; Viannia braziliensis
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.12123

The leishmaniasis is a spectral disease caused by the protozoan Leishmania spp., which threatens millions of people worldwide. Current treatments exhibit high toxicity, and there is no vaccine available. The need for new lead compounds with leishmanicidal activity is urgent. Considering that many lead leishmanicidal compounds contain a quinoidal scaffold and the thiazole heterocyclic ring is found in a number of antimicrobial drugs, we proposed a hybridization approach to generate a diverse set of semi‐synthetic heterocycles with antileishmanial activity. We found that almost all synthesized compounds demonstrated potent activity against promastigotes of Leishmania (Viannia) braziliensis and reduced the survival index of Leishmania amastigotes in mammalian macrophages. Furthermore, the compounds were not cytotoxic to macrophages at fivefold higher concentrations than the EC50 for promastigotes. All molecules fulfilled Lipinski's Rule of Five, which predicts efficient orally absorption and permeation through biological membranes, the in silico pharmacokinetic profile confirmed these characteristics. The potent and selective activity of semi‐synthetic naphthothiazoles against promastigotes and amastigotes reveals that the 2‐amino‐naphthothiazole ring may represent a scaffold for the design of compounds with leishmanicidal properties and encourage the development of drug formulation and new compounds for further studies in vivo. The embedment of 2‐aminothiazole fragment into naphthoquinoidal structures led to discovery of safe and effective leishmanicidal compounds against promastigote and amastigote stages of Leishmania braziliensis, with very good drug‐like properties and probable oral bioavailability.