Design, synthesis and biological evaluation of novel tetrasubstituted quinoline-3-carboxamides derivatives

Abstract

Quinolines are well known naturally occurring heterocyclic compounds with nitrogen as a heteroatom. Quinolines are also one of the major classes of naturally occurring compounds and the interest in their chemistry is due to the wide range of their biological activities. The objective of the project was the synthesis of novel tetra-substituted quinoline-3carboxamides and subsequent transformation to other novel derivatives and evaluation of their biological activities against malaria and cytotoxicity. In achieving the objective, 2-chloroquinoline-3-carbaldehyde analogues 54A-G were synthesised from the reaction of acetanilides 53A-G and acetic acid. Knoevenagal reaction of 2chloroquinoline-3-carbaldehydes 54A-G with thiazolidinedi-2,4-one 62 provided 2chloroquinoline-3-methylene thiazolidinedi-2,4-one 55A-G which then underwent nucleophilic substitution reaction with sodium azide and afforded (Z)-5-((tetrazolo [1,5a] quinoline-4-yl) methylene) thiazolidinedi-2,4-one 56A-F. (Z)-ethyl-2-(2-5-((7bromotetrazolo [1,5a] quinolin-4-yl) methylene-2,4-dioxothiazolidin-3-yl) acetamido) acetate 57 was synthesised from the reaction of (Z)-5-((7-bromotetrazolo [1,5a] quinoline-4-yl) methylene) thiazolidinedi-2,4-one 56D and ethyl-2-(2-chloroacetamido) acetate 65. The structures of the compounds were characterised by 1D NMR (1H, 13C, and DEPT 135), IR spectroscopy, elemental analysis and high-resolution mass spectroscopy. Novel selected synthesised quinoline compounds were evaluated of in vitro for two biological assays; namely anti-malarial activity and cytotoxicity. The anti-malaria activities of the novel quinoline compounds against 3D7 strain of the malaria parasite Plasmodium falciparum displayed that 2,6-dichloroquinoline-3-methylene thiazolidinedi-2,4-one 55C, (Z)-5-((7-fluorotetrazolo [1,5a] quinoline-4-yl) methylene) thiazolidinedi-2,4-one 56B and (Z)-5((7-ethoxytetrazolo [1,5a] quinoline-4-yl) methylene) thiazolidinedi-2,4-one 56F are potential malaria drugs since they reduced the percentage parasite viability to 25.80, 12.40 and 20.40 respectively. These results were further substantiated by their IC50 values 0.40, 0.04 and 0.50 µg/mL. Compound 56B displayed the highest cytotoxicity activity against human cervix adenocarcinoma cells displaying percentage viability of 14.22 %. Compounds 56F and 56C displayed moderate cytotoxicity activity at 56.60 and 59.81 % viability.