Synthesis, characterisation and antibacterial activity of new quinoline and quinoxaline hybrid molecules.

Abstract

This thesis focussed on the synthesis of three series of hybrid molecules, all related to the quinoline or quinoxaline scaffolds. These are (i) 2-(1H-benzo[d]imidazol-2-yl)quinolines, (ii) quinoxaline-chalcones and their pyrazoline derivatives, and (iii) 5-(quinolin-2-ylmethylene)- 2-thioxothiazolidin-4-ones. The target molecules were fully characterized particularly by 2D NMR and verified by high resolution mass spectrometry. The synthesised compounds were tested for their antibacterial activity against two Gram +ve species, Staphylococcus aureus and MRSA and four Gram -ve bacteria, Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli and Salmonella typhimurium to identify lead compounds which could be developed into active pharmaceutical ingredients for antibiotics. A total of fifty-six compounds were synthesised based on these scaffolds. The 2-(1H-benzo[d]imidazol-2-yl)quinolines were synthesised by the Doebner-Miller reaction of crotonaldehyde and substituted anilines, followed by oxidation and benzimidazole formation with o-phenylenediamine. The series of compounds consisted of 6- and 8- substituted halogen, methoxy and methyl groups. A complete structural elucidation of all compounds was carried out and the effects that the different substituents had on the resonances of the quinoline scaffold reported. The quinoxaline-chalcone and quinoxaline-chalcone-quinoline hybrids were synthesised from a quinoxaline acetophenone derivative and various 2- or 4- substituted benzaldehydes and 6- or 8- substituted quinoline-2-carbaldehydes via the Claisen-Schmidt condensation. These molecules were then converted to their respective pyrazoline derivatives using hydrazine hydrate. The 5-(quinolin-2-ylmethylene)-2-thioxothiazolidin-4-ones were synthesised from the Knoevenagel reaction of various 8- and 6-substituted quinoline-2- carbaldehydes and rhodanine. The method described is a convenient way to tag a rhodanine moeity onto a quinoline ring.Of the three sets of compounds synthesised, only the quinoxaline-chalcone-quinoline hybrids showed appreciable antibacterial activity, being active against the Gram +ve S. aureus and MRSA and not against the Gram -ve species, with the activity against S. aureus being much higher than that for MRSA. Quinoxaline chalcones showed no activity against the bacterial strains tested, however, when a quinoline moiety replaced the aromatic ring, eight derivatives showed enhanced antibacterial activity, having MBC values between 0.151-0.360 M against S. aureus and 10.9-618 M against MRSA. The quinoxaline-chalcone-quinoline hybrids showed antibacterial activity two orders of magnitude greater than ciprofloxacin and levofloxacin against S. aureus and comparable activity to these standards against MRSA. Interestingly, the 4'-Br and 4'-Cl pyrazoline derivatives of the quinoxaline chalcones (having MBC values of 11 and 12 M, respectively) showed comparable activity to levofloxacin and ciprofloxacin.