| dc.description.abstract | Tuberculosis (TB) has scourged humankind for hundreds of years. Not only are millions of people infected and killed by this disease annually, but more than a quarter of the world’s population is living with latent TB. Mycobacterium tuberculosis (Mtb), the causative pathogen of TB, is effortlessly spread when a person with the active diseases coughs, spits, sings or sneezes, propelling the pathogen into the air. TB not only affected ten million people in 2017, but proved fatal to 1.6 million infected that same year, of which 0.3 million were co-infected with human immunodeficiency virus (HIV) making TB the leading killer of HIV-positive people.
TB disease is in fact curable, but it is the rise of multi- and extensively- drug-resistant strains of Mtb that renders the control and effective treatment of the disease challenging. Currently only 55 % of multidrug-resistant TB patients are treated successfully and, to make matters worse, second-line chemotherapy options used to treat these cases are not only expensive and toxic, but also extensive. Extensive regimens create an opening for various other disadvantages, such as patient non-adherence and therefore treatment failure and relapse. This can in turn lead to the emergence of drug. There is, therefore, an urgent need for novel effective and affordable anti-mycobacterial agents with better safety profiles to curb TB more efficiently.
In search for such agents a series of eleven novel hybrids linking directly hydroquinone and triazole moieties were investigated. The series was synthesised in a two-step process, starting with nucleophilic substitution SN2 reaction of commercial benzoquinone with sodium azide in acidic medium to form an azido intermediate. This was followed by Huisgen’s copper-catalysed alkyne-azide cycloaddition ‘click’ chemistry of the intermediate with various alkynes to afford targeted hybrids in low to good yields (23 – 70 %). Routine characterisation techniques such as infrared spectrometry, nuclear magnetic resonance, and high resolution mass spectrometry, were used to confirm the structures of the hybrids. The purities were determined by means of high performance liquid chromatography and were found to be in the 92 – 98 % range.
The anti-mycobacterial activity of the hybrids was assessed in vitro against the human virulent H37Rv strain of Mtb. Cytotoxicity of the synthesised hybrids were evaluated using human embryonal kidney cells (HEK-293).
In general, the hybrids were nontoxic to the mammalian cells, but were either inactive or possessed poor anti-mycobacterial activity. Hybrid 14, featuring a thiobenzyl substituent on the triazole ring and with cLogP 3.03, was the most active of all. It possessed MIC90 16 μM and showed no toxicity to kidney cells, but was poorly selective for mycobacteria with a selectivity index, SI = 6, which disqualifies it as a potential anti-mycobacterial hit.
A leading explanation to the overall insignificant anti-mycobacterial activities of these hybrids could be attributed to their structural rigidity conferred by the lack of linker between the quinol and triazole rings. It is this rigidity that obstructs the passage of the hybrids through the bacterium cell wall, thus preventing them from reaching the targeted site within Mtb. The impact of the linker on the biological activity may be elucidated through future investigation of flexible hybrids. | en_US |
