TY - JOUR
T1 - Novel prenyloxy chalcones as potential leishmanicidal and trypanocidal agents
T2 - Design, synthesis and evaluation
AU - Espinoza-Hicks, José C.
AU - Chacón-Vargas, Karla Fabiola
AU - Hernández-Rivera, Jessica L.
AU - Nogueda-Torres, Benjamín
AU - Tamariz, Joaquín
AU - Sánchez-Torres, Luvia Enid
AU - Camacho-Dávila, Alejandro
N1 - Publisher Copyright:
© 2019 Elsevier Masson SAS
PY - 2019/4/1
Y1 - 2019/4/1
N2 - The available drugs for treating Leishmaniasis and American trypanosomiasis have high toxicity and multiple side effects, among other problems. More effective and less toxic treatments are urgently needed. A series of chalcones that contained a prenyloxy or geranyloxy substituent was synthesized and characterized. Each substituent was attached to the A ring in some compounds and to the B ring in others, with additional substituents placed on the chalcone moiety. The present aim was to evaluate the effect of the substitution pattern on leishmanicidal and trypanocidal activity. When tested at a single concentration, the compounds exerting a metabolic inhibition close to or exceeding 50% for Leishmania mexicana were 11, 17 and 12, and for Trypanosoma cruzi were 11, 17, 15 and 26. Upon determining the selectivity index (SI =IC50/CC50), the values were 80.9, 1.24 and 55.12 for 11, 17 and 12 (respectively) versus L. mexicana, and 75.1, 1.43, 27.36 and 33.52 for 11, 17, 15 and 26 (respectively) versus T. cruzi. Structural isomers 11 and 17 showed activity for both the L. mexicana and T. cruzi strains, though the greater cytotoxic activity of 17 led to a lower SI. Compounds 12, 15 and 26 were species specific. For T. cruzi, the SI was higher for 11, 15 and 26 than for the reference drugs nifurtimox and benznidazole. The examination of promastigote morphology after exposing L. mexicana and T. cruzi to 11 revealed a decrease in cell density. The current findings suggest that 11 could be a useful lead compound for further SAR studies.
AB - The available drugs for treating Leishmaniasis and American trypanosomiasis have high toxicity and multiple side effects, among other problems. More effective and less toxic treatments are urgently needed. A series of chalcones that contained a prenyloxy or geranyloxy substituent was synthesized and characterized. Each substituent was attached to the A ring in some compounds and to the B ring in others, with additional substituents placed on the chalcone moiety. The present aim was to evaluate the effect of the substitution pattern on leishmanicidal and trypanocidal activity. When tested at a single concentration, the compounds exerting a metabolic inhibition close to or exceeding 50% for Leishmania mexicana were 11, 17 and 12, and for Trypanosoma cruzi were 11, 17, 15 and 26. Upon determining the selectivity index (SI =IC50/CC50), the values were 80.9, 1.24 and 55.12 for 11, 17 and 12 (respectively) versus L. mexicana, and 75.1, 1.43, 27.36 and 33.52 for 11, 17, 15 and 26 (respectively) versus T. cruzi. Structural isomers 11 and 17 showed activity for both the L. mexicana and T. cruzi strains, though the greater cytotoxic activity of 17 led to a lower SI. Compounds 12, 15 and 26 were species specific. For T. cruzi, the SI was higher for 11, 15 and 26 than for the reference drugs nifurtimox and benznidazole. The examination of promastigote morphology after exposing L. mexicana and T. cruzi to 11 revealed a decrease in cell density. The current findings suggest that 11 could be a useful lead compound for further SAR studies.
KW - Chalcones
KW - Leishmania
KW - Metabolic inhibition
KW - Selectivity index
KW - Structure-activity relationship
KW - Trypanosoma cruzi
UR - http://www.scopus.com/inward/record.url?scp=85061582341&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2019.02.028
DO - 10.1016/j.ejmech.2019.02.028
M3 - Artículo
C2 - 30784876
SN - 0223-5234
VL - 167
SP - 402
EP - 413
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
ER -