Evaluation of Novel Nicotine Analogues for their Anti-Bacterial and Anti-Fungal Activity

Microbes like bacteria and fungi are known to cause several human illnesses. Amongst those various diseases, certain bacterial and fungal infections are more common because of their tendency to develop new strains under any circumstances by developing resistance against the existing drugs and decontamination methods currently employed. This alarms the scientists for continuously exploring alternate molecules to control these illnesses. Several nicotinic derivatives were, evaluated for their antibacterial and anti-fungal activity. The nicotinic acid moiety with characterized de-addiction property exhibited antimicrobial activity against various pathogens of clinical importance. One compound (5-(4-fluorophenyl) nicotinoyl)-1-methylpyrrolidin-2-one developed in the present study was found very effective against Candida albicans, a highly pathogenic opportunistic fungus responsible for 80-95% vaginal infection in humans and has developed resistance to several antifungals. Therefore, this class of compounds could be a good starting point to develop new lead compounds for handling this pathogenic fungus. In addition, the broad-spectrum anti-microbial action of nicotine analogues developed in the present study may find immense applications in formulating new disinfection or decontamination strategies against widely spreading pathogens of clinical significance.

Novel nicotine analogues with potential anti-mycobacterial activity

Tuberculosis (TB) is the second leading lethal infectious disease in the world after acquired immuno deficiency (AIDs). We have developed a series of twenty-five novel nicotine analogues with de-addiction property and tested them for their activity against Mycobacterium tuberculosis (MTB). In an effort to increase the specificity of action and directing nicotine analogues to target MTB, four promising compounds were further optimized via molecular docking studies against the Dihydrofolate reductase of MTB. After lead optimization, one nicotine analogue [3-(5-(3fluorophenyl)nicotinoyl)-1-methylpyrrolidin-2-one] exhibited minimum inhibitory concentration of 1 μg/mL (2.86 nM) against M. tuberculosis (H37Rv strain), a human pathogenic strain of clinically significant importance. Pharmacokinetic analysis of [3-(5-(3fluorophenyl)nicotinoyl)-1methylpyrrolidin-2-one] with lowest MIC value via oral route in Wistar rats revealed that at a dosage of 5 mg/kg body weight gave a maximum serum drug concentration (Cmax) of 2.86 μg/mL, Tmax of one hour and a half-life (T1/2) of more than 24 h and Volume of distribution (Vd) of 27.36 L. Whereas the parenteral (intra venous) route showed a Cmax of 3.37 μg/mL, Tmax of 0.05 h, T1/2 of 24 h and Vd equivalent to 23.18 L. The acute oral toxicity and repeated oral toxicity studies in female Wistar rats had an LD50>2000 mg/kg body weight. Our data suggests that nicotine derivatives developed in the present study has good metabolic stability with tunable pharmacokinetics (PK) with therapeutic potential to combat MTB. However, further in vivo studies for anti-tuberculosis activity and elucidation of mode of action could result in more promising novel drug for treating MTB. To the best of our knowledge this is the first report revealing the anti-mycobacterial potential of nicotine analogue at potential therapeutic concentrations.