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.

Identification of chalcone-based antileishmanial agents targeting trypanothione reductase / Ortalli, Margherita; Ilari, Andrea; Colotti, Gianni; De Ionna, Ilenia; Battista, Theo; Bisi, Alessandra; Gobbi, Silvia; Rampa, Angela; Di Martino, Rita M.C.; Gentilomi, Giovanna A.; Varani, Stefania; Belluti, Federica*. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - STAMPA. - 152:(2018), pp. 527-541. [10.1016/j.ejmech.2018.04.057]

Identification of chalcone-based antileishmanial agents targeting trypanothione reductase

Ortalli, Margherita;Bisi, Alessandra;Gobbi, Silvia;Rampa, Angela;Di Martino, Rita M. C.;Gentilomi, Giovanna A.;Varani, Stefania;Belluti, Federica
2018

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.
2018
Identification of chalcone-based antileishmanial agents targeting trypanothione reductase / Ortalli, Margherita; Ilari, Andrea; Colotti, Gianni; De Ionna, Ilenia; Battista, Theo; Bisi, Alessandra; Gobbi, Silvia; Rampa, Angela; Di Martino, Rita M.C.; Gentilomi, Giovanna A.; Varani, Stefania; Belluti, Federica*. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - STAMPA. - 152:(2018), pp. 527-541. [10.1016/j.ejmech.2018.04.057]
Ortalli, Margherita; Ilari, Andrea; Colotti, Gianni; De Ionna, Ilenia; Battista, Theo; Bisi, Alessandra; Gobbi, Silvia; Rampa, Angela; Di Martino, Rita M.C.; Gentilomi, Giovanna A.; Varani, Stefania; Belluti, Federica*
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/636030
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