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Infectious diseases such as tuberculosis and leishmaniasis are leading causes of human death. One of the major factors contributing to the poor control of these diseases is primarily the reduced effectiveness of the existing chemotherapies as result of the increasing rise of multidrug-resistant strains of their causative agents. This leads to the imperative need to develop new and effective drugs. In search for such agents, a series of hydroquinone-triazole hybrids was investigated. The design, synthesis, and biological activities against the human virulent H37Rv strain of Mycobacterium tuberculosis (Mtb) and Leishmaniasis major (L. major), causative pathogen of human cutaneous leishmaniasis, are herein reported. The hybrids were synthesized following a two-step process Michael addition and Click chemistry. They were found to be noncytotoxic toward human kidney embryonic cells but expressed poor cellular antileishmanial and antimycobacterial activities. Hybrid 14, 2‐{4‐[(phenylsulfanyl)methyl]‐1H‐1,2,3‐triazol‐1‐yl}benzene‐1,4‐diol, was the most active among synthesized molecules, with MIC90 16 and IC50 23 µM against Mtb and L. major parasite, respectively, but had a poor safety profile, being as toxic to mammalian cells as to mycobacteria and parasites. Thus, compound 14 did not stand as potential anti-infective hit for further investigation. Future endeavor will focus on the investigation of more rigid and flexible hybrids of both scaffolds in order to assess the impact a spacer might have on their biological activity.

The increasing prevalence of multidrug-resistant strains of Mycobacterium tuberculosis (Mtb), the pathogen of human tuberculosis (TB), serves as a strong incentive for the discovery and development of new agents for the treatment of this plight. In search for such drugs, we investigated a series of benzyltriazole derivatives. We herein report the design, synthesis and biological activity of disubstituted benzyltriazoles against the human virulent H37Rv strain of Mtb as well as the toxicity on human embryonic kidney (HEK-293) cells. The derivative 21 featuring trifluoromethyl substituent in para position on the phenyl ring and n-butyl chain in position 4 on the triazole ring was the most active with MIC90 and MIC99 values of 1.73 and 3.2 µM, respectively, in the albumin-free medium. It also displays high selectivity towards bacteria growth inhibition (SI > 58), thus stands as a better hit for further investigation, including lead optimization, DMPK parameters determination and assessment of its activity in animal models.

The emergence of drug-resistant tuberculosis (DR-TB) as well as the requirement for long, expensive and toxic drug regimens impede efforts to control and eliminate TB. Therefore, there’s a need for effective and affordable anti-mycobacterial agents which can shorten the duration of therapy and are active against Mycobacterium tuberculosis (Mtb) in both active and latent phases. Nitrofurantoin (NFT) is a hypoxic agent with activity against a myriad of anaerobic pathogens and, like the first-line TB drug, rifampicin (RIF), kills non-replicating bacilli. However, the poor ability of NFT to cross host cell membranes and penetrate tissue means that it does not reach therapeutic concentrations. To improve TB efficacy of NFT, a series of NFT analogues was synthesized and evaluated in vitro for anti-mycobacterial activity against the laboratory strain, Mtb H37Rv, and for potential cytotoxicity using human embryonic kidney (HEK-293) and Chinese hamster ovarian (CHO) cells. The NFT analogues showed good safety profiles, enhanced anti-mycobacterial potency, improved lipophilicity, as well as reduced protein binding affinity. Analogue 9 which contains an eight carbon aliphatic chain was the most active, equipotent to isoniazid (INH), a major front-line agent, with MIC90 = 0.5 μM, 30-fold more potency than the parent drug, nitrofurantoin (MIC90 = 15 μM), and 100-fold more selective towards mycobacteria. Therefore, 9 was identified as a validated hit for further investigation in the urgent search for new, safe and affordable TB drugs.

Tuberculosis is the deadliest infectious disease affecting humankind with a death toll of approximately 1.7 million people in 2016. The increasing prevalence of multidrug-resistant strains of the causative pathogen, Mycobacterium tuberculosis (Mtb) which results in reduced effectiveness of the current therapies, underscores the urgent need for the development of new antitubercular drugs. In the search for such drugs, we investigated two series of ciprofloxacin (CPX) derivatives (analogues and hybrids). We herein report the design, synthesis, and biological activity of these series against the human virulent Mtb H37Rv strain in vitro. The small propionyl analogue 11 (MIC90 1.6 μM; SI > 61) and the large cholesteryl hybrid 32 (MIC90 2.0 μM; SI > 6) were the most active derivatives, comparable to CPX (MIC90 1.8 μM). However, the slightly less active but non-cytotoxic para-fluorobenzyl hybrid 28 (MIC90 3.7 μM; SI 27) was more selective toward bacteria than 32. Thus, the CPX derivatives 11 and 28 were identified as preferred antitubercular hits for further investigation including distribution, metabolism and pharmacokinetic parameters determination and in vivo activity assessment in animal models.

MSc (Pharmacy Chemistry), North-West University, Potchefstroom Campus, 2019. Tuberculosis (TB) is a public health crisis – infecting a quarter of the world’s population, also, inflicting 10.4 million morbidities and 1.7 mortalities in 2016. TB is effortlessly acquired through the inhalation of droplets containing the bacilli Mycobacterium tuberculosis (Mtb) from an infected individual. The occurrence of multi-, extensively-, and totally drug-resistant strains of Mtb, co-infection with human immunodeficiency virus (HIV), and the complex, prolonged and substantial treatment regimen with its associated side-effects result in poor patient compliance and creates an irrefutable demand for the development of novel antimycobacterial agents to address these issues. Within this body of work, the skeleton of a second-line antimycobacterial agent, i.e. ciprofloxacin (CPX), was utilised to devise a new chemical entity with potent antimycobacterial activity. However, poor solubility and the rise of resistance against the fluoroquinolones class of drugs was recognised as a major drawback associated with CPX that requires improvement. Two series of CPX derivatives were synthesised, with each series a different strategy in mind for targeting Mtb. In Series 1 (analogues), CPX was derivatised in position N-15 and/or further modifications were made by replacing the hydroxyl-group in position C-11 of the carboxylic acid, with either an ester or an amide. In Series 2 (hybrids), hybrid drugs – consisting of CPX and 1,2,3-traizole (chosen for its reported antimycobacterial activity) – were prepared when utilising Huisgen’s copper alkyne-azide cycloaddition ‘‘click’’ reaction. In both series, cholesterol was employed as targeting moiety since it gets taken up by Mtb who uses it as energy (carbon) source after metabolism. Anchoring CPX to cholesterol will result in the transport of the active drug into the bacterium through the mce4-transporter. Characterisation of all synthesised compounds was achieved by means of nuclear magnetic resonance (NMR), mass spectrometry (MS), infrared spectrometry (IR), and the purity of compounds determined with the help of high performance liquid chromatography (HPLC). Both series of compounds were assessed in vitro for their antimycobacterial activity against the human virulent H37Rv strain of Mtb in the commonly employed Middlebrook 7H9 Broth base media, using either a GFP or MABA reported assay. Overall, analogues with the carboxylic acid retained in position C-3 were mostly found to be active (MIC90 < 10 μM), the amides inactive (MIC90 >125 μM) and the esters had mixed activities (MIC90 1 – 125 μM). The analogues containing the highly lipophilic cholesteryl moiety were mostly inactive. The activity of these fluoroquinolones was revealed in fact to be structure specific. This was equally seen with the hybrids. Additionally, the structure-activity relationship (SAR) revealed the least electron donating or withdrawing the substituent on the phenyl ring the more anti-Mtb active the hybrid. Cytotoxicitities of synthesised compounds were assessed using normal human fetal lung fibroblast (WI38), human embryonic kidney cells (HEK-293), and Chinese hamster ovary (CHO) mammalian cell lines. The active analogues 9, 10, 11 and 13, and the hybrids 26, 28, 29, 30 and 32 were nontoxic towards these cell lines, with selectivity indices (SI) greater than 10 – showing high specificity towards Mtb. On account of the efficacy and safety criteria, analogues 10 and 11 and hybrid 28 with MIC90 below 10 μM, and SI-values greater 27 were the most promising hit candidates lending themselves for further development. National Research Foundation (NRF) Masters