Identification of chalcone-based antileishmanial agents targeting trypanothione reductase

Margherita Ortalli, Andrea Ilari, Gianni Colotti, Ilenia De Ionna, Theo Battista, Alessandra Bisi, Silvia Gobbi, Angela Rampa, Rita M.C. Di Martino, Giovanna A. Gentilomi, Stefania Varani, Federica Belluti

Risultato della ricerca: Contributo su rivistaArticolo in rivistapeer review

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.

Lingua originaleInglese
pagine (da-a)527-541
Numero di pagine15
RivistaEuropean Journal of Medicinal Chemistry
Volume152
DOI
Stato di pubblicazionePubblicato - 25 mag 2018
Pubblicato esternamente

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