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Microwave Assisted Synthesis of New Pyrazinamide Analogues and their Biological Evaluation
* 1 , 1 , 1 , 2 , 2
1  Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, 50005 Hradec Kralove, Czech Republic
2  Faculty of Natural Sciences, Comenius University, Mlynska Dolina Ch-2, 84215 Bratislava, Slovakia

Abstract: Through last decades tuberculosis has been becoming more and more dangerous ever before. Although the number of new cases has been falling since 2006, new epidemiological problem has appeared with mycobacterial stems, which are becoming increasingly resistant to current treatment, and with more frequent HIV co-infection. All these consequences lead to effort to invent highly effective and innovative drugs. [1] One of the first-line antituberculotic drugs is pyrazinamide (PZA). This small molecule together with its unique chemical properties is very good template and is suitable for another modifications. Two series of PZA derivatives were prepared in this research project. Two starting compounds (3-chloropyrazine-2-carboxamide and 5-chloro-6-methylpyrazine-2,3-dicarbonitrile) were treated with a various group of on-ring substituted benzylamines. All the reactions took place in microwave reactor with focused field due to higher yields and shorter reaction time (experimentally verified). Products of these aminodehalogenational reactions were chemically characterized (melting point, IR and 1H, 13C NMR spectra, log P and elemental analysis) and then in vitro biological screenings were carried out. Antimycobacterial evaluation was completed using pyrazinamide and isoniazide as standards against various Mycobacterium species. Next screening was testing the herbicidal activity of prepared compounds. [2] The principle is measuring the inhibition of photosynthetic electron transport in spinach chloroplasts (Spinacia oleracea L.) using Hill reaction. DCMU (Diurone®) was taken as a standard and inhibition concentration (IC50) was determined. An experiment with artificial electron donor 1,5-diphenylcarbazide was performed for determining the site of action of the studied compounds in photosynthetic apparatus. Fluorescence measurements were also used to monitor the interaction of pyrazine derivatives with residues of aromatic amino acids present in the photosynthetic apparatus proteins. The major part of substances showed good herbicidal activity and there is a possibility of prediction structure-activity relationships (SAR) according to lipophilicity (π) and electronic properties (σ). The last screening included antibacterial and antifungal tests against eight antibacterial and eight fungal stems. Standards – neomycin, bacitracin, penicillin G, ciprofloxacin, phenoxymethylpenicillin, amphotericin B, voriconazole, nystatin, fluconazole. Minimal inhibition concentration (MIC) was determined as IC90. Few substances have shown small activity against various tested stems but it is not enough to predict SAR. References: [1] Progress, WHO Global Tuberculosis Control Report 2011, WHO/HTM/TB/2011.16,, accessed October 3, 2012. [2] Dolezal, M.; Kralova, K. Synthesis and Evaluation of Pyrazine Derivatives with Herbicidal Activity, Herbicides, Theory and Applications, Sonia Soloneski and Marcelo L. Larramendy (Ed.), 2011, ISBN: 978-953-307-975-2, InTech
Keywords: Microwave assisted synthesis; Pyrazinamide; Tuberculosis; Biological screening; Herbicidal activity