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New Potentially Active Pyrazinamide Derivatives Synthesised Under Microwave Conditions
* 1 , 1 , 2 , 3 , 3
1  Faculty of Pharmacy in Hradec Kralove, Charles University, Heyrovskeho 1203, 50005 Hradec Kralove, Czech Republic
2  Department of Microbiology, University Hospital in Hradec Kralove, Sokolska 581, 50005 Hradec Kralove, Czech Republic
3  Faculty of Natural Sciences, Comenius University, Mlynska Dolina Ch-2, 84104 Bratislava, Slovakia

Abstract: Pyrazinamide (PZA) is one of the most important molecules in the world. It is counted among the first-line antituberculotic drugs together with rifampicin, isoniazide, ethambutol or streptomycine. Using it as anti-tubercular agent it can shorten the time needed for treatment by two thirds and acts as sterilising drug. On the other hand, due to its small molecule and unique chemical properties, that makes this compound very suitable for structural modifications, new ways of use have appeared, such as antiviral, herbicidal, antibacterial, antineoplastic activities.There was prepared a series of 3-chloropyrazine-2-carboxamide, which is a derivative of PZA, and was treated with a group of aliphatic, alicyclic amines and saturated heterocycles containing nitrogen. All the final compounds were prepared using microwave reactor with focused field according to the experimentally set conditions. This approach was chosen according to higher yields, shorter reaction times and better conversion.Every product of this type of aminodehalogenation reaction was characterized chemically by melting point, 1H, 13C NMR and IR spectra, elemental analysis and lipophilicity (calculated and experimentally set). In vitro biological screenings followed.Antimycobacterial evaluation has been made against 4 mycobacterial strains (M. tuberculosis, M. kansasii and 2 strains of M. avium) and isoniazide has been used as a standard. Next screening has been focused on antibacterial and antifungal tests against 8 bacterial and 8 fungal stems. There have been used 5 antibiotics (neomycin, bacitracin, penicillin G, ciprofloxacin, phenoxymethylpenicillin) and 4 antimycotics (amphotericin B, voriconazole, nystatin, fluconazole) as standards. Minimal inhibition concentration has been set as 90% inhibition resp. 50% inhibition of control. The last evaluation has been focused on testing of herbicidal activity of these new compounds. The main principle of this measurement has been the inhibition of photosynthetic electron transport in chloroplasts that have been taken from spinach (Spinacea oleracea). The Hill reaction has been used together with DCMU (Diurone®) as standard. Inhibition concentration IC50 has been recorded and the determination of site of action in photosynthetic apparatus (PA) of studied compounds has been performed using an artificial electron donor 1,5-diphenylcarbazide. Fluorescence measurements have been also used for monitoring the interaction of PZA analogues with amino acids residues present in PA.The results showed some antifungal activities but it was not enough to predict any structure-activity relationships. On the contrary, there was found a conspicuous relationship between lipophilicity and herbicidal activity in the aliphatic amines group.
Keywords: Amines, Carboxamide, Microwave assisted reaction, Pyrazinamide, Tuberculosis