Design, Synthesis of Biaryl Piperidine Derivatives and Their Evaluation as Potential Antileishmanial Agents against Leishmania donovani Strain Ag83

Abstract

We have developed a new series of simple biaryl piperidine derivatives (11-19) based on biaryl naphthylisoquinoline alkaloid Ealamine-A. The target compounds were synthesized, analyzed by spectral data, and evaluated for antileishmanial activity against Leishmania donovani strain Ag83 by MTT assay. The compounds have shown the best to moderate antileishmanial activity. The 5'-fluoro-2'-methoxyphenyl derivative 14 and 3',5'-difluorophenyl derivative 16 have inhibited the promastigotes by 86 % and 85 % after 24 h and 92 % and 91 % after 48 h incubation, respectively, at 400 μM concentration. The % inhibition was lower with the lowering of the concentration and increased with the incubation time. Compounds 12, 15, and 18 have solubility issues and proved to be less active than the rest of the compounds. Molecular docking studies were performed on selective active compounds and the results indicate that these compounds may act by binding to the Leishmanolysin and the docking scores are in good correlation with the antileishmanial activity. These results provide an initial insight into the design of new therapeutics for neglected tropical diseases.

Challenges and Tools for In Vitro Leishmania Exploratory Screening in the Drug Development Process: An Updated Review

“…Indeed, there are many colorimetric assays that are usable, simple, inexpensive, and suitable for large-scale screening [43,44]. Some of those are poorly illustrated in the existing literature, such as the trypanothione reductase assay [45] or acid phosphatase assay [46][47][48][49], while others are widely proven, notably, those related to intracellular metabolizing salts such as the most famous MTT assay (3-(4,5-dimethylthiazol-2-yl-2,5-diphenyl tetrazolium bromide) [38,[50][51][52][53][54][55][56][57][58][59]. This yellow salt is reduced to purple formazan crystals in living cells, allowing for easy determination of parasite viability.…”