title: In vitro antileishmanial activity of novel azoles (3-imidazolylflavanones) against promastigote and amastigote stages of Leishmania major.
abstract: Leishmaniasis is a protozoan infectious disease widely distributed all around the world. First line drugs including antimoniales are insufficient due to resistance in endemic areas and high toxicity. Azole antifungals like ketoconazole (KCZ) are also used as antileishmanial agents for several decades. In the present study, we evaluated in vitro antileishmanial effects of new azole antifungals namely 3-imidazolylflavanones (IFs) and their oximes (IFOs) against Leishmania major (L. major) parasites. The obtained results showed remarkable effect of our compounds on promastigote and amastigote stages of L. major. In particular, the 4-chloro analog of flavanone (IF-2) and 3-chloro substituted flavanone oxime (IFO-3) with IC50values ≤8.9μg/mL were 8-fold more potent than KCZ (IC50=72μg/mL) against promastigote form of L. major. In amastigote stage, the compounds IF-2 and IFO-2 decreased the mean number of infected macrophages (MIR) more than KCZ (p<0.005). In addition, compounds IF-1, IF-2, IF-4, IFO-2, IFO-3 and IFO-5 decreased the mean number of amastigotes per macrophages (MNAPM) significantly more than KCZ (p<0.005). All compounds decreased both MIR and MNAPM significantly more than control (p<0.001). Compounds IF-2 and IFO-2 with parasite survival of 7.70% and 20% had the highest inhibition on intracellular amastigotes. Although most of compounds displayed acceptable selectivity index, compound IF-2 had the highest CC50value (115.4μg/mL) and SI (383.3). We concluded that our new synthetic azoles displaying potent activity against L. major could be considered as new hits for drug development in the field of antileishmanial therapy.
authors.affiliation: Student Research Committee, Department of Parasitology and Mycology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran; Molecular and Cell Biology Research Center, Department of Parasitology and Mycology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.
authors.forename: Azar
authors.initials: A
authors.lastname: Shokri
authors.affiliation: Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.
authors.forename: Saeed
authors.initials: S
authors.lastname: Emami
authors.affiliation: Molecular and Cell Biology Research Center, Department of Parasitology and Mycology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran. Electronic address: mahdif53@yahoo.com.
authors.forename: Mahdi
authors.initials: M
authors.lastname: Fakhar
authors.affiliation: Clinical Research Development Center of Children Hospital, Hormozgan University of Medical Sciences, Bandar Abbas, Iran.
authors.forename: Saeed Hosseini
authors.initials: SH
authors.lastname: Teshnizi
authors.affiliation: Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.
authors.forename: Masoud
authors.initials: M
authors.lastname: Keighobadi
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D044950:Flavanones / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D018320:Leishmania major / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects; D010091:Oximes / Q000494:pharmacology
chemical_list: D000981:Antiprotozoal Agents; D044950:Flavanones; D007093:Imidazoles; D010091:Oximes
keywords: Amastigote; Antileishmanial agents; Azole antifungals; Flavanones; Leishmania major; Promastigote