<i>In Vitro</i> Evaluation of the Antimalarial Activity of a Designed Novel Quinuclidine Derivative

Abstract

A simple Schiff base, N-(pyridine-4-yl-methylene) quinuclidine-3-amine was synthesized from 3-aminoquinuclidine and 4-pyridine carboxaldehyde. The physico-chemical properties of the synthesized compound were studied. Molecular docking study was carried out and the quinuclidine derivative was evaluated for its in vitro antimalarial activity against chloroquine-sensitive Plasmodium falciparum strain. Although higher dose of synthesized compound was required for antimalarial activity (EC 50 = 13.125 g/ml) in comparison to chloroquine (EC 50 5.144 g/ml), the correlation coefficient confirmed good fit of the data. Furthermore, the result of the molecular docking provided insights into the ligand-protein interactions responsible for the inhibitory potency.Keywords: Antimalarial, docking, HPLC, Plasmodium falcipurum, quinuclidine, mass, NMR.MALARIA, a disease affecting large populations, has proved to be an obstacle in the cultural and socioeconomic progress of society in the tropical and subtropical world. It is widespread in all parts of India except in areas, which are not favourable for transmission and multiplication of malaria parasites [1][2][3][4][5][6] . Quinine, the oldest known antimalarial, led to the discovery of chloroquine, the most widely used antimalarial drug for almost more than half a century. However, chloroquine has lost its importance as an antimalarial due to widespread drug resistance 7,8 . Quinolines, however, are still considered as important lead structures and several researchers have been working on synthesis of their analogues 9 . Quinolines interact and form a non-covalent complex with heme and also inhibit the synthesis of hemozoin. On the other hand, quinuclidine(1-azabicyclo [2.2.2]octane), synthesized by Loffler and Stieze in 1909, is a structural component of some biomolecules, including quinine 10,11 . Although development of a new drug candidate against a specific disease is a difficult task, with the help of informatics-driven chemistry, it is now fairly easy. However, in silico prediction of biological activity is not always reflected in the biological system.In view of the resistance developed by malarial parasites and considering the biological activity of quinuclidine moiety-bearing biomolecules, a simple Schiff base carrying the quinuclidine structural component was designed 12 . Accordingly, N-(pyridine-4-yl-methylene) quinuclidine-3-amine (C) was synthesized (Scheme 1) from 3-aminoquinuclidine (A) and 4-pyridine carboxaldehyde (B). On the basis of the results of in silico antimalarial activity study, in vitro study was carried out for antimalarial activity of this Schiff base. The results of this study are promising and would help in the development of novel antimalarial drugs.All the reactions were carried out in borosilicate glassware with proper precautions. The solvents and reagents were synthesis-grade chemicals procured commercially and used as such without further tests and purification. Chemical structures have been drawn in ChemDraw version 7.0.1. Melting point ...

Virtual Screening, Molecular Docking and QSAR Studies in Drug Discovery and Development Programme

“…Molecular docking studies are usually performed on free like AutoDock (Art Olsen, David Goodsell, Scripps), and commercial software packages such as Discovery Studio (Accelrys), Glide (Schrodinger), GOLD (CCDC) and FlexX (BiosolveIT). The crystal structures of protein molecules of interest are retrieved from the RCSB Protein Data Bank (https://www.rcsb.org) 31,32 . The methodology involved in molecular docking is depicted in Figure 4.…”

Synthesis and Antimalarial Activity of Lawsone Mannich Base Derivatives

“…21,22,23 Two strains were used for the study, one is CQ-sensitive 3D-7 and the other is CQ-resistant RKL-2. All the test compounds, 4a-j were initially screened at two fixed doses, 5 µg/ml and 50 µg/ml against CQ-sensitive strain.…”

Heterogeneous Acid Catalyzed Synthesis and Spectroscopic Characterization of Schiff Bases Derived from Chalcone Derivatives

“…Schiff base, which was named after Hugo Schiff [1], was prepared via condensation reaction between amino functionality and an aldehydic/ketonic carbonyl [2]. The medicinal potential of Schiff bases in drug designed is quite evident in their reported diverse pharmacological properties which include antimicrobial [3], anticancer [4], antitumor [5], anti-convulsant [6], antimalarial [7], antitubercular [8], anti-HIV, anti-inflammatory [9], antidepressant activities among others [10]. Their enhanced reported bioactivity might be as a result of their improved lipophilic character thereby improving their bioavailability in the lipid membranes; therefore, resulting in growth redundancy in the organism [11].…”