Synthesis, characterisation and antibacterial activity of new quinoline and quinoxaline hybrid molecules.
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Date
2018
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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.
Description
Doctoral Degree. University of KwaZulu-Natal, Durban.