Biological Evaluation and Mechanistic Studies of Quinolin-(1 H )-Imines as a New Chemotype against Leishmaniasis

Abstract

Leishmaniasis is one of the most challenging neglected tropical diseases and remains a global threat to public health. Currently available therapies for leishmaniases present significant drawbacks and are rendered increasingly inefficient due to parasite resistance, urging the need for more effective, safer, and cheaper drugs. In our efforts to identify novel chemical scaffolds for the development of antileishmanial agents, we have screened in house antiplasmodial libraries against axenic and intracellular forms of Leishmania infantum, L. amazonensis and L. major. Several of the screened compounds showed IC50 values against intracellular L. infantum parasites in the submicromolar range (1h: IC50 0.9 μM and 1n: IC50 0.7 μM) and selectivity indexes of 11 and 9.7, respectively. Compounds also displayed activity against L. amazonensis and L. major, albeit in the low micromolar range. Mechanistic studies revealed that 1n efficiently inhibits oxygen consumption and significantly decreases the mitochondrial membrane potential in L. infantum axenic amastigotes, suggesting that this chemotype acts, at least in part, by interfering with mitochondrial function. Structure-activity analysis suggests that 1n is a promising antileishmanial lead and emphasize the potential of the quinoline-(1H)-imine chemotype for the future development of new antileishmanial agents.

Structure–Activity Relationship Studies of 9-Alkylamino-1,2,3,4-tetrahydroacridines against Leishmania (Leishmania) infantum Promastigotes

“…The bone marrow-derived macrophages (BMDM) used in our work were obtained following the protocol described by Gomes-Alves and colleagues [ 16 ]. In brief, bone marrow (BM) cells were recovered from femurs and tibias of BALB/c mice and differentiated to macrophages in Dulbecco’s modified Eagle’s medium (DMEM; Gibco ® Life Technologies Thermo Fisher, Waltham, MA, USA), supplemented with 10% heat-inactivated FBS, 1% minimum essential medium-nonessential amino acids solution (MEM; Gibco ® Life Technologies Thermo Fisher, Waltham, MA, USA), 50 U/mL penicillin, 50 μg/mL streptomycin (complete DMEM medium [cDMEM]) and 20% L929 cell-conditioned medium (LCCM) as a source of the macrophage-colony stimulating factor (M-CSF).…”

Ultrasound assisted synthesis and spectral correlations of some bio-active E-imines

“…The -N = CH-moiety and presence of polar substituents are the origin for the biological activities of E-imines. Schiff's bases possess vast number of bio-activities such as antimicrobial [24,25], antiviral, anti-HIV [30], anti-in ammatory [31], anti-tumor [32], anti-fertility [33], anti-plasmodial [34], anti-leishmanial [35], cardio vascular [36], anti-cancer [37] and anti-malarial [38][39][40][41][42]. Guillon et al reported the synthesis, design and antimalarial potency of some novel bis{N-[(pyrrolo[1,2-a]quinoxalin-4-yl)benzyl]-3-aminopropyl}amine derivatives [38]..Ressurreição et.…”