Recent Progress in the Development of Indole-Based Compounds Active against Malaria, Trypanosomiasis and Leishmaniasis

Abstract

Human protozoan diseases represent a serious health problem worldwide, affecting mainly people in social and economic vulnerability. These diseases have attracted little investment in drug discovery, which is reflected in the limited available therapeutic arsenal. Authorized drugs present problems such as low efficacy in some stages of the disease or toxicity, which result in undesirable side effects and treatment abandonment. Moreover, the emergence of drug-resistant parasite strains makes necessary an even greater effort to develop safe and effective antiparasitic agents. Among the chemotypes investigated for parasitic diseases, the indole nucleus has emerged as a privileged molecular scaffold for the generation of new drug candidates. In this review, the authors provide an overview of the indole-based compounds developed against important parasitic diseases, namely malaria, trypanosomiasis and leishmaniasis, by focusing on the design, optimization and synthesis of the most relevant synthetic indole scaffolds recently reported.

A Minireview on the Scope of Cadogan Cyclization Reactions Leading to Diverse Azaheterocycles

“…Indole skeleton plays an important role in drug discovery as it exhibits diverse medicinal properties [36] such as anticancer, antifungal, antimalarial, antitubulin and many more. [37] Various synthetic approaches [4,38] have been used for the construction of an indole ring, among which Cadogan cyclization happens to be a convenient method to access the indole nucleus. [1] In 2019, Sahu et al performed one-pot two fold C3-alkenylation between pyrroles and aldehydes by using Brønsted acid and base to get indole-based molecules 61 a-b through Cadogan cyclization as the final step (Scheme 14).…”

“…Indole skeleton plays an important role in drug discovery as it exhibits diverse medicinal properties [36] such as anticancer, antifungal, antimalarial, antitubulin and many more [37] . Various synthetic approaches [4,38] have been used for the construction of an indole ring, among which Cadogan cyclization happens to be a convenient method to access the indole nucleus [1] .…”

A recent update on new synthetic chiral compounds with antileishmanial activity

“…Moreover, as shown with (+)-spiroindimicin A, indole containing compounds have been widely studied against leishmania for their antiparasitic activities. 52,53 Recently, Nogueira, Sousa and co-workers studied the activity of indoles having a pyrazino[2,1-b]quinazoline-3,6-dione functionality against Plasmodium falciparum, T. brucei, and L. infantum. 54 The synthesis of the most active compound 53 is reported in Scheme 7 55 and essentially followed a Mazurkiewicz-Ganesan approach.…”

Synthesis and Biological Evaluation of Sclareolide-Indole Conjugates and Their Derivatives

“…Despite these recent achievements, to the best of our knowledge, neither sclareolide-indole conjugate nor sclareolide-polyphenol conjugate has been reported, as shown in Figure 1 . In view of the interesting biological activities of sclareolide and its derivatives, we aimed to synthesize novel sclareolide derivatives containing various indoles or polyphenol methyl ethers, given their high prevalence in bioactive compounds and drugs [ 19 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ]. As part of our ongoing interest [ 29 ] in finding natural product derivatives with potent antitumor activities, we herein report our synthesis and the biological evaluation of a new series of sclareolide-indole conjugates and their derivatives.…”