Identification of chalcone-based antileishmanial agents targeting trypanothione reductase

Abstract

All currently used first-line and second-line drugs for the treatment of leishmaniasis exhibit several drawbacks including toxicity, high costs and route of administration. Furthermore, some drugs are associated with the emergence of drug resistance. Thus, the development of new treatments for leishmaniasis is a priority in the field of neglected tropical diseases. The present work highlights the use of natural derived products, i.e. chalcones, as potential source of antileishmanial agents. Thirty-one novel chalcone compounds have been synthesized and their activity has been evaluated against promastigotes of Leishmania donovani; 16 compounds resulted active against L. donovani in a range from 3.0 to 21.5 μM, showing low toxicity against mammalian cells. Among these molecules, 6 and 16 showed good inhibitory activity on both promastigotes and intracellular amastigotes, coupled with an high selectivity index. Furthermore, compounds 6 and 16 inhibited the promastigote growth of other leishmanial species, including L. tropica, L. major and L. infantum. Finally, 6 and 16 interacted with high affinity with trypanothione reductase (TR), an essential enzyme for the leishmanial parasite and compound 6 inhibited TR with sub-micromolar potency. Thus, the effective inhibitory activity against Leishmania, the lack of toxicity on mammalian cells and the ability to block a crucial parasite's enzyme, highlight the potential for compound 6 to be optimized as novel drug candidate against leishmaniasis.

Curcumin-1,2,3-Triazole Conjugation for Targeting the Cancer Apoptosis Machinery

“…It has been acknowledged that design strategies based on "privileged sub-substructures" combination are a powerful tool to generate promising lead compounds [25]. The fluorine functionalization strategy demonstrated its pivotal role in providing valuable bioactive lead compound in several therapeutic areas [26][27][28].…”

Functionalization of the Chalcone Scaffold for the Discovery of Novel Lead Compounds Targeting Fungal Infections

“…In an effort to uncover new starting points for antifungal drug discovery, an in-house small library of chalcone-based analogues (Table 1) was screened against C. albicans, as a continuation of our exploration of this privileged scaffold as suitable template for developing anti-infective agents. Indeed, some members of the library have been previously tested versus Leishmania donovani [17], and a number of compounds endowed with encouraging in vitro activity were identified. To gain insight into the key features for eliciting the antifungal effect, the chemical variability of the chalcones regarded the substitution patterns of the A- and B-rings, as depicted in Figure 1, resulting in Series I, II, and III.…”

Biological Role of Chalcones in Medicinal Chemistry

“…Leishmaniasis is spread through sand flies of the genus Phlebotomus, primary hosts being the vertebrates. The chalcone (60) was evaluated against 29 promastigotes of Leishmania donovani exhibiting low toxicity against mammalian cells [62].…”