Search for novel antifungal compounds among arylamides of 1,2,4-triazinyl-6-propanecarboxylic acid

Abstract

In sti tute of mo lec u lar bi ol ogy and ge net ics NAS of Ukraine Academicain Zabolotnog str., 150, Kyiv, 03680 Ukraine shved_@ imbg.org. ua De sign and syn the sis of a set of 3,5-dioxy-1,2,4-triazinyl-6-propionic acid (TPA) arylamides were de veloped in or der to search for new com pounds with fungistatic prop er ties on the ba sis of azapyrimidine de riv atives. Carboxamides ca pa ble to block tran scrip tion were re vealed among ob tained com pounds us ing T7 RNA-pol model test-sys tem in vi tro, and the only de riv a tives con tain ing halogene-substituent in pharmacophore part showed the in hib i tory prop er ties. The model of vir tual tri ple non-pro duc tive com plex at poly mer ase cat a lytic site (in hib i tor-en zyme-DNA tem plate) was pro posed, il lus trat ing a pos si ble mech anism of in hib i tory ac tion of such com pounds on RNA syn the sis. Pre lim i nary screen ing of new triazine de riva tives re vealed their in hib i tory ac tion against some kinds of fungi and bac te ria.Keywords: 1,2,4-triazine de riv a tives, syn the sis, sup pres sion of tran scrip tion, T7 RNA-pol, antifungal ac tivity. 441ISSN 0233-7657. Biopolymers and cell. 2007. vol. 23. N 5. Translated from Ukrainian.

Synthesis and study on biological activity of nitrogen-containing heterocyclic compounds – regulators of enzymes of nucleic acid biosynthesis

“…After the screening in T7 pol system the samples of compounds -efficient transcription inhibitors -were investigated for the antibacterial, antifungal, antituberculosis and antiviral activity. Among three dozens of investigated PCA amides there were three compounds, the antifungal activity of which regarding the strains of Ñandida albicans was higher than that of the well-known medical preparation diflucan (fluconazole) [15]. 21 compounds from the series of N-arylamides of PCA-1 demonstrated antituberculosis activity regarding the wild strain Mycobacterium tuberculosis with minimal inhibitory concentration (MIC) in the range of 0.5-2.7 µM, i. e. at the level of the effect of isoniazid and rifampicin (MIC of 1.4 and 0.95 µM, respectively).…”

“…The capability of 1,2,4-triazine derivatives to play the role of «universal base», capable of forming strong complexes with canonic Thy, Ade, Cyt, Gua, prompted us to perform triazine-based synthesis of the hybrid compounds with phenazine-1-carboxylic acid (PCA-1; 2) -non-nucleoside inhibitors [14]. At the same time, taking into account pharmacophoric properties of carboxamide group, we developed convenient methods of obtaining the series of N-substituted amides of triazinyl-6-propanecarboxylic acid (PCA; 3) [15,16] and N-arylamides of PCA-1 (4) [17].…”

“…The system simulating the transcription, based on DNA-dependent RNA-polymerase of bacteriophage T7 (T7pol), was adapted for accelerated testing new compounds for biological activity [15][16][17][18][19]. The advantages of this model are its availability, synthesis productivity, plain quantitative determination of results, the possibility of simultaneous testing of dozens of substances in different variants of experiments and estimation of the affinity of compounds to DNA-matrix, the enzyme or to the transcriptional complex.…”