Antileishmanial activity of imidothiocarbamates and imidoselenocarbamates

Abstract

In the present study, a family of 15 imidothio- and imidoselenocarbamates (1-15) analogs have been synthesized and screened for their in vitro antileishmanial potential against Leishmania infantum promastigotes. The six most active ones (2, 4, 7, 13, 14, and 15) were also tested in an axenic amastigote model. In order to establish their selectivity indexes (SI) the cytotoxic effect of each compound was also assayed against Jurkat and THP-1 cell lines. Compounds 2 and 4, both with a pyridine moiety, showed a moderate antileishmanial activity with an IC(50) value of 4.68 ± 0.46 and 3.03 ± 0.24 μM, respectively, in the amastigote model. The activity was compared with that of standard drugs, edelfosine (IC₅₀ = 0.82 ± 0.13 μM) and miltefosine (IC₅₀ = 2.84 ± 0.10 μM). Related to selectivity, the SI of both compounds are similar to those of the standard drugs when compared against the THP-1 cell line. Moreover, compound 4 was able to reduce the number of amastigote-infected THP-1 cells to 40% of that observed in untreated controls after a 96-h period of treatment. These derivatives thus represent two new leads for further studies aimed at establishing their mechanism of action.

The effect of verapamil on in vitro susceptibility of promastigote and amastigote stages of Leishmania tropica to meglumine antimoniate

“…For clinical and persistent cases of CL, the choice of second-line drugs is very limited due to prolonged length of therapy and adverse reactions , even though there are promising new compounds used alone or in combination (Moreno et al 2011;Prasad et al 2000;Shakya et al 2011;Tafaghodi et al 2011). Treatment failure is common in many endemic areas (Firooz et al 2006;Khatami et al 2007;Modabber et al 2007).…”

“…The first-line drugs, antimonials, are less effective against various forms of leishmaniasis and resistance is emerging (Jha 2006;Moreno et al 2011;Pour et al 2011). For clinical and persistent cases of CL, the choice of second-line drugs is very limited due to prolonged length of therapy and adverse reactions , even though there are promising new compounds used alone or in combination (Moreno et al 2011;Prasad et al 2000;Shakya et al 2011;Tafaghodi et al 2011).…”

Leishmania major protein disulfide isomerase as a drug target

“…Failure of classic chemotherapy that lies on the use of antimonial compounds as well as risks of transmission of drug resistance highlight the priority to develop novel chemotherapeutic approaches to fight the disease (Ait-Oudhia et al 2011;Santos et al 2008). Current trials which show promising results cover natural and biologically active products (Karamian et al 2007; Morais et al 2011;Moreno et al 2011;Mussi et al 2007;Shakya et al 2011;Zhang et al 2010).…”

Novel Heteroaryl Selenocyanates and Diselenides as Potent Antileishmanial Agents

“…On the other hand, the incorporation of selenium into novel nanomaterials has demonstrated effectiveness in the treatment of leishmaniasis (20). We have reported (21)(22)(23)(24) new selenium compounds with potent in vitro antiparasitic activity against Leishmania infantum and Leishmania major, and selectivity indexes higher than those observed for the reference drugs miltefosine, edelfosine, and paromomycin. Additionally, some of them induced nitric oxide production and alterations in gene expression profiling related to proliferation (PCNA), treatment resistance (ABC-transporter and ␣-tubulin), and virulence (QDPR) (23).…”