Design, Synthesis and In Vitro Trypanocidal and Leishmanicidal Activities of 2‐(2‐Arylidene)hydrazono‐4‐oxothiazolidine‐5‐acetic Acid Derivatives

Abstract

Trypanosomatids are protozoan parasites responsible for leishmaniasis, Chagas disease and sleeping sickness. The design of new antitrypanosomatid drugs with trypanosomicidal and leishmanicidal activities is an effective perspective. The thiazolidinone ring is an important scaffold for several biological disorders. Herein, 4‐oxothiazolidine‐5‐acetic acids (1 a‐1 w) have been synthesized from respective thiosemicarbazone and maleic anhydride. Some of these 4‐oxothiazolidine‐5‐acetic acids were toxic for trypomastigotes without affecting macrophages viability. From this series, compounds 1 e (IC50=10 μM), 1 u (IC50=8.94 μM), 1 g (IC50=5.65 μM) and 1 w (14.06 μM) showed the best anti‐T. cruzi activity for trypomastigote form, while 1 e, 1 u and 1 g showed SI higher than benznidazole (BZD). Similarly, against epimastigote the compound 1 q (IC50epi= 4.70 μM) has been found more selective and most active than benznidazole. However, evaluation against T. cruzi revealed that most of the active compounds have a low inhibition profile and weak leishmanicidal activity. In silico data suggests a good drug‐likeness profile, high chemical stability and demonstrate the use of these compounds in the designing of new anti‐T. cruzi and anti‐Leishmanial drugs.

The design, synthesis, and in vitro trypanocidal and leishmanicidal activities of 1,3-thiazole and 4-thiazolidinone ester derivatives

“…The methyl substitution on the aromatic ring was evidenced as a good change, resulting in satisfactory IC 50 values in both synthesized positions ( ortho and para ), as well as the methoxy substitution. In addition, the two leading compounds were ortho -substituted in terms of the trypanocidal activity of both series, evidencing the importance of this position and corroborating our previous results with the non-cyclized 1g* (IC 50 = 5.65 μM), 27 which presents an o -chlorine substitution.…”

“…Moreover, our strategy of esterification was proven to be efficient since the outstanding carboxylic acids synthesized by our group had their activity greatly improved, to enumerate: 1b* (IC 50 L.ama = 34.48 μM, IC 50 L.inf = 59.52 μM) p -bromine substituted that was esterified to 2d, and 1c* (IC 50 L.inf = 85.30 μM), p -chlorine that originated from 2b. 27 …”

“…Some of these reported compounds showed potent trypanocidal activity and low toxicity to mammalian cells. 27 …”

“…Herein, we present two novel series, exploring the bioisosteric strategy on thiosemicarbazones cyclization to 1,3-thiazoles/4-thiazolidinones rings and developing a novel derivatives from the carboxylic acids produced by our group. 27 The hypothesis was based on the concept of whether the classical medicinal chemistry using esterification could be used to simultaneously improve the solubility and permeability to obtain acetates. In two different series, we used a simple two-step synthesis approach to obtain novel 1,3-thiazoles (1a–k) and 4-thiazolidinones (2a–p) from the thiosemicarbazones nucleus, as summarized in Fig.…”

“…The utmost promising molecule was chosen to assess necrosis development on trypomastigotes by flow cytometry assay and evaluation of activity against the intracellular forms of T. cruzi , as well as evaluation of its ultrastructural impacts on T. cruzi trypomastigotes, seen by scanning electron microscopy (SEM). All data were collected to establish the structure–activity relationships (SAR), and provide a comparison with the previous results of their bioisosteric analogues 27 and reference drugs. Hence, our work demonstrates that 1,3-thiazoles and 4-thiazolidinone acetates are a versatile building block for lead generation, easily yielding access to diverse derivatives for drug optimization.…”