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.
Aim. Search for compounds with antibacterial and antiviral properties among N-arylamides of 9-substituted phenazine-1-carboxylic acids (PCA), inhibitors of the RNA synthesis. Methods. Influence of N-aryl-amides on the RNA synthesis was tested in vitro in the model system of the DNA-dependent RNA polymerase of phage T7 (T7 RNAP). Antimicrobial activities of the N-arylamides against bacteria Erysipelothrix rhusiopathiae VR-2 var. IVM, Klebsiella spp. and Escherichia coli ATCC25922 were investigated by the method of two-fold dilution in a liquid medium. Antiviral effects against Bovine Viral Diarrhea Virus (BVDV) and cytotoxicity of the N-arylamides were evaluated using Madin-Darby bovine kidney (MDBK) cells. Results. Twenty N-arylamides appeared to be efficacious inhibitors of the RNA synthesis at concent- rations of 0.48–61 µМ. The compound 16 proved to be the most effective inhibitor of T7 RNAP with the IC50 value being 0.48 µМ. Fourteen N-arylamides demonstrated antibacterial properties against gram positive and gram negative bacteria at the 0.1–10 µg/ml concentrations. A number of the N-arylamides revealed a multiplicity of their antimicrobial actions: 7 compounds against two bacteria and two compounds, 2 and 3, against three bacteria investigated. N-arylamides 16 and 26 showed high inhibitory activity as to BVDV with the IC50 values 0.43 and 0.88 µg/ml and SI values 160 and 10 correspondingly. Conclusions. The obtained data evidence that the most likely targets of the N-arylamides 9-substituted PCA in bacteria and viruses are their RNA synthesizing complexes
To study a series of new acridine derivatives containing two basic fragments able to bind to quadruplex DNA at C-4 and C-9 positions as potential telomerase inhibitors. Methods. TRAP assay was used to determine the activity of compounds in vitro. Results. A number of acridines inhibiting the enzyme at micromolar concentrations were found, with IC 50 = 2.6 µM for the most active compound. Conclusions. The introduction of a highly basic N,N-dimethylaminoalkyl group at the C-9 position of the acridine core results in a strong increase of biological activity of compounds, and a 5-methyl substituent further enhances it.
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