Analysis of 5-nitrofuraldehyde derivatives antimicrobial activity, evaluation of toxicity, pharmacokinetic properties and structure – activity relationship

Analysis of 5-nitrofuraldehyde derivatives antimicrobial activity, evaluation of toxicity, pharmacokinetic properties and structure – activity relationship. K. Gaivelytė Master Thesis. Scientific supervisors: Dr. V. Petrikaitė, Dr. J. Šarlauskas, Prof. Habil. Dr. A. Pavilonis; Kaunas University of Medicine, Faculty of Pharmacy, Department of Medicinal Chemistry. Kaunas, 2010. The Aim of the Research – to evaluate the influence of the structure of 5-nitrofuraldehyde derivatives and identify the most promising compounds for the further research. Methods. Prognosis of antimicrobial activity of all compounds was carried out by using PASS software. Antimicrobial activity was tested in vitro by using a serial dilution in agar technique. Pharmacokinetic properties and toxicity were predicted by using ADME/Tox Boxes program. Results. PASS program predicted antibacterial and antifungal activity for all tested compounds. The results of experiments in vitro showed that activity against various microorganisms was different; compounds without nitrofuran fragment were not active. Biscompouds were active enough against all bacteria (MIC = 0,5-100 μg/ml), except P. aeruginosa, K. pneumoniae and P. mirabilis. Biscompoud possessing butyl fragment in its structure was the most active against S. aureus, E. faecalis and B. subtilis and biscompound BIC-67 with the moiety of pyridine was the most active against K. pneumoniae, P. aeruginosa, P. mirabilis (MIC = 50 μg/ml). It could be that the activity of this compound (BIC-67) is influenced not only by the presence of heterocycle, but also by its double (bis) structure. Compound BIC-22 having dichlorbenzene moiety connected through the oxygen bridge in its structure selectively and in low concentration (MIC = 10 μg/ml) inhibited the growth of B. subtilis. Halogenation of benzene moiety in the side chain of 5-nitrofuran derivatives increased the activity against C. albicans compared to nitrofural. The lower toxicity was predicted for biscompounds (except compound BIC-67) and for the most active antimicrobial compound having furanyl moiety (BIC-24) compared to nitrofural. High probability of toxicity to organs was predicted for the biscompounds, and these probabilities were lower for the compound BIC-24. Toxicity of 5 nitrofurans increases almost two times after chain lengthening by the double bond in the second position, however antimicrobial activity increases, too. Toxicity to organs increases by increasing the number of nitro groups in the structure of 5-nitrofuran derivatives. The structure of nitrofuran bisderivatives and incorporation of benzimidazole moiety into nitrofuran structure may lead to their low bioavailability, so it is not advisable to develop compounds with similar structure for oral use. Conclusions. Prognosis of activity is useful because it helps to identify the compounds for testing but it is not advisible to rely in it completely; it is necessary to carry out the experiments in vitro. On the basis of the results of microbiological experiments and the prognosis data for toxicity and pharmacokinetic properties we identified the most promising nitrofuran derivatives: BIC-22, BIC-24, BIC 34, BIC-67