Abstract

Human African trypanosomiasis (HAT) and Chagas disease are neglected tropical diseases (NTDs) due to parasite protists from the Trypanosoma genus transmitted by insect vectors. Trypanosomiases affect mostly poor populations in the developing countries, and the development of new antitrypanosomal drugs is underinvested by governments and the pharmaceutical industry. In this chapter, we described the development of 4-thiazolidinone and thiazole derivatives with heterocyclic fragments which exhibit good inhibition of trypanosome growth and might constitute potential candidates for the development of new drugs against trypanosomiasis. Antitrypanosomal design, mainly within structure-based design, led to the synthesis of 5-ene-4-thiazolidinone-3-alkanecarboxylic acids; 2,3-disubstituted 4-thiazolidinones; thiazolidinone-pyrazoline, phenylindole-thiazolidinone, and imidazothiadiazole-thiazolidinone hybrids; as well as 4-thiazolidinone-based fused heterocycles, especially thiopyrano[2,3-d]thiazoles, and non-thiazolidinone compounds–namely, isothiocoumarine derivatives. Moreover, antitrypanosomal 4-thiazolidinones are of special interest in the search for new antimalarial and antileishmanial agents. Also many active anticancer agents among the abovementioned 4-thiazolidinones have been discovered.

Highlights

  • Trypanosomatid infections belong to the neglected tropical diseases (NTDs)–a group of communicable diseases spread in 149 countries in the tropical and subtropical regions of the globe and affecting more than 1 billion people [1]

  • Human trypanosomiasis is caused by kinetoplastids, flagellated protists of Trypanosoma genus transmitted by an insect vector [3]

  • Thiazolidinone derivatives are more active than the known thiosemicarbazone analogues

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Summary

Introduction

Trypanosomatid infections belong to the neglected tropical diseases (NTDs)–a group of communicable diseases spread in 149 countries in the tropical and subtropical regions of the globe and affecting more than 1 billion people [1]. An important advance was the development of the nifurtimox-eflornithine combination therapy (NECT), which has became the standard first-line treatment for the second stage of T.b. gambiense HAT [20, 21]. In the case of contraindications to nifurtimox, eflornithine may be given as a monotherapy for T.b. gambiense HAT (meningoencephalitic stage), but it is not recommended for T.b. rhodesiense disease [4, 24]. According to new WHO guidelines, under particular conditions, fexinidazole may replace pentamidine as first-line treatment in patients with the first stage of T.b. gambiense HAT and replace nifurtimox-eflornithine combination therapy as first-line treatment in patients with the second stage of T.b. gambiense HAT with fewer than 100 cerebrospinal fluid white blood cells per μL These recommendations cannot be applied for the treatment of patients younger than 6 years or with a bodyweight less than 20 kg [31, 32]. One more new oral compound developed for treatment of all stages of T.b. gambiense HAT is acoziborole being at late Phase II/III of clinical trials [31]

Chagas disease
Drug discovery strategies
Trypanosomatid peptidases
Nitroreductases
Dolicholphosphate mannose synthase
Dihydrofolate reductase
Trypanothione reductase
Kinases
Triosephosphate isomerase
Farnesyl diphosphate synthase
Cyclic nucleotide-specific phosphodiesterases
1.3.10 Lanosterol 14α-demethylase
Fused heterocyclic molecules based on the core 4-thiazolidinone
Findings
Conclusion
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