TY - JOUR
T1 - Identification of chalcone-based antileishmanial agents targeting trypanothione reductase
AU - Ortalli, Margherita
AU - Ilari, Andrea
AU - Colotti, Gianni
AU - De Ionna, Ilenia
AU - Battista, Theo
AU - Bisi, Alessandra
AU - Gobbi, Silvia
AU - Rampa, Angela
AU - Di Martino, Rita M.C.
AU - Gentilomi, Giovanna A.
AU - Varani, Stefania
AU - Belluti, Federica
N1 - Publisher Copyright:
© 2018 Elsevier Masson SAS
PY - 2018/5/25
Y1 - 2018/5/25
N2 - 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.
AB - 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.
KW - Chalcone
KW - Drug discovery
KW - Leishmaniasis
KW - Natural products
KW - Neglected tropical disease
KW - Trypanothione reductase
UR - http://www.scopus.com/inward/record.url?scp=85046800808&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2018.04.057
DO - 10.1016/j.ejmech.2018.04.057
M3 - Article
SN - 0223-5234
VL - 152
SP - 527
EP - 541
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
ER -