Synthesis, In Silico, and In Vitro Evaluation of Anti-Leishmanial Activity of Oxadiazoles and Indolizine Containing Compounds Flagged against Anti-Targets

2019
Authors
Stevanović, StrahinjaSencanski, Milan
Danel, Mathieu
Menendez, Christophe
Belguedj, Roumaissa
Bouraiou, Abdelmalek
Nikolić, Katarina

Cojean, Sandrine
Loiseau, Philippe M.
Glisić, Sanja

Baltas, Michel
Garcia-Sosa, Alfonso T.

Article (Published version)
Metadata
Show full item recordAbstract
Due to the lack of approved vaccines against human leishmaniasis and the limitations of the current chemotherapy inducing side effects and drug resistance, development of new, effective chemotherapeutic agents is essential. This study describes the synthesis of a series of novel oxadiazoles and indolizine-containing compounds. The compounds were screened in silico using an EIIP/AQVN filter followed by ligand-based virtual screening and molecular docking to parasite arginase. Top hits were further screened versus human arginase and finally against an anti-target battery to tag their possible interactions with proteins essential for the metabolism and clearance of many substances. Eight candidate compounds were selected for further experimental testing. The results show measurable in vitro anti-leishmanial activity for three compounds. One compound with an IC50 value of 2.18 mu M on Leishmania donovani intramacrophage amastigotes is clearly better positioned than the others as an interes...ting molecular template for further development of new anti-leishmanial agents.
Keywords:
Leishmania / arginase / in silico / anti-target / in vitro / anti-leishmanial inhibitors / anti-targetSource:
Molecules, 2019, 24, 7Publisher:
- MDPI, Basel
Projects:
DOI: 10.3390/molecules24071282
ISSN: 1420-3049
PubMed: 30986947