Nitrothiazole-thiazolidinone hybrids : synthesis and in vitro antimicrobial evaluation

Abstract

Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis (Mtb), is one of the world’s most fatal infectious diseases. Annually, 10 million people fall ill with TB and 1.5 million people die from it globally. TB control and management solely rely on the use of drugs, most of which were developed 40–60 years ago. The emergence and spread of drug-resistant Mtb strains, as well as toxicity associated with these drugs create an irrefutable demand for novel drugs with potent activity against active and latent TB infections. Treatment can take up to 4–9 or 18–24 months with a cocktail of first- and second-line antitubercular drugs, depending on Mtb drug susceptibility. This often results in patients not complying with their antitubercular treatments, which is the major cause of treatment failure or relapse. Novel oral drugs that may shorten treatment regimens while still achieving complete Mtb clearance would have a positive influence on patient compliance, slowing the onset of disease as well as the evolution of drug-resistant Mtb strains. In addition to Mtb, other pathogenic bacteria commonly referred to as ESKAPE pathogens are also currently seen as a global public health threat. In the last decade, the prevalence of antimicrobial-resistant (AMR) bacteria in hospitals has increased, as has the challenge of hospital-acquired infections (HAIs). The majority of HAIs include central line-associated bloodstream infections, catheter-associated urinary tract infections, surgical site infections, and ventilator-associated pneumonia, all of which are linked to a high prevalence of multidrug-resistant pathogens known as ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.). In addition, ESKAPE pathogens are also wreaking havoc on many areas of individual patient healthcare, including increased direct health care expenses, increased length of hospitalisation, and higher fatality rates. The identification of new antimicrobial drugs with activity against drug-resistant ESKAPE pathogens is vital and urgent since treatment

options for them are rapidly becoming limited. Indeed, if no new antimicrobial is discovered promptly, it is predicted that no drug will be available to treat AMR bacteria by 2050. Nitazoxanide (NTZ), an antimicrobial agent harbouring a 5-nitrothiazole moiety, has been demonstrated to have activity against both replicating and non-replicating Mtb through a novel mechanism of action. Thiazolidin-4-one is another well-known privilege scaffold with possible substitution sites at the second, third, and fifth positions of its heterocyclic ring system. With this in mind, the molecular hybridisation strategy has been employed in this study as a rational design strategy for generating novel ligands or prototypes in which the pharmacophoric subunits in the molecular structure of NTZ and the biologically active thiazolidin-4-ones were merged to produce novel hybrid compounds with a possible poly-pharmacological mechanism of action. In this study, 17 novel nitrothiazole-thiazolidinone hybrids were synthesised and evaluated in vitro against Mtb and certain ESKAPE pathogens. Compounds were also screened for antifungal activity against Candida albicans. The hybrids were synthesised using a multi-step synthetic protocol that includes N-acylation, dehydrative cyclization (S-alkylation and intermolecular cyclization), and Knoevenagel condensation. The condensation of different electron withdrawing and electron donating benzylidene moieties in the fifth position (C5) of the thiazolidin-4-one scaffold was used to investigate the structure-activity relationship of the hybrids. After purification, the hybrid-target compounds were synthesised in yields ranging from 26% to 69%. However, the poor solubility of the hybrid-target compounds in standard solvents such as dichloromethane, ethanol, or methanol was recognised as a limitation in this work, emphasising the need for optimisation in future research. Nuclear magnetic resonance (1H and 13C), high resolution mass spectrometry, and Fourier-transform infrared spectroscopy were used to characterise all synthesised hybrids, and the purity of the compounds was assessed using high performance liquid chromatography. Finally, the target compounds were

tested for overt cell toxicity against human embryonic kidney cells (HEK-293) and haemolysis against whole human red blood cells (RBCs). All hybrid compounds displayed remarkable antitubercular activity of < 0.24 – 2.00 μM. Most compounds had low micromolar activity against S. aureus and C. albicans. Compound 3b, in particular, demonstrated sub-micromolar activity against Mtb and C. albicans while also having superior activity against methicillin-resistant Staphylococcus aureus (MRSA) (< 0.25 μg/ml) as compared to the reference drug vancomycin (1 μg/ml). Compound 3g had activity against C. albicans (≤ 0.25 μg/ml) comparable to that of the drug fluconazole (0.12 μg/ml). The antimicrobial SAR reveals that ortho substitution of the C5-benzylidene moiety favours activity against S. aureus.