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The cell wall of <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) has a unique structural organisation, comprising a high lipid content mixed with polysaccharides. This makes cell wall a formidable barrier impermeable to hydrophilic agents. In addition, during host infection, <i>Mtb</i> resides in macrophages within avascular necrotic granulomas and cavities, which shield the bacterium from the action of most antibiotics. To overcome these protective barriers, a new class of anti-TB agents exhibiting lipophilic character have been recommended by various reports in literature. Herein, a series of lipophilic heterocyclic quinolone compounds was synthesised and evaluated in vitro against pMSp12::GFP strain of Mtb, two protozoan parasites (<i>Plasmodium falciparum</i> and <i>Trypanosoma brucei brucei</i>) and against ESKAPE pathogens. The resultant compounds exhibited varied anti-<i>Mtb</i> activity with MIC₉₀ values in the range of 0.24–31 µM. Cross-screening against <i>P. falciparum</i> and <i>T.b. brucei</i>, identified several compounds with antiprotozoal activities in the range of 0.4–20 µM. Compounds were generally inactive against ESKAPE pathogens, with only compounds <b>8c</b>, <b>8g</b> and <b>13</b> exhibiting moderate to poor activity against <i>S. aureus</i> and <i>A. baumannii</i>.