Voloshchuk O. Antimicrobial and antiviral activity of adamantane (alcyl, cycloalkyl) derivatives of aminopropanol-2

The dissertation is devoted to the problem of finding new compounds with antimicrobial and antiviral activity among the adamantane (alkyl, cycloalkyl) derivatives of aminopropanol-2 and selection of the most promising applicants for creation of antimicrobial and antiviral agents on their basis. From 53 test compounds of four groups (adamantyl, boryl (norbornyl) containing, with cyclic and alicyclic substituents in the alkoxy group) 44 were newly synthesized. Their antimicrobial and antiviral potential was demonstrated with in silico method. The antimicrobial activity of the investigated compounds against the collection and clinical strains of microorganisms was determined in vitro. At low concentrations inhibited the growth of collection strains and clinical isolates of staphylococci and fungi of the genus Candida compound № 6 (with MIC values from 7.8 μg / ml to 15.6 μg / ml) and compound №10 (with MIC values from 15.6 μg / ml to 31.25 μg / ml). The MIC of compound № 11 in relation to the studied collection strains of enterobacteria was at the level of MIC of the reference drug ofloxacin (in the range from 1.9 μg / ml to 3.9 μg / ml). According to PASS prediction for compounds № 6 and № 10 the value of Pa inhibitory activity of peptidoglycan glycosyltransferase ranges from 0.352 to 0.520. For compound № 11 Pa / Pi inhibitory activity of peptidoglycan glycosyltransferase is 0.352 / 0.075. Most empirically established "structure-antimicrobial activity" relationships have been confirmed and supplemented by the results of hierarchical clustering of the structural components of the compounds depending of microbial effects. The cytotoxic effect on the HEp-2 cells of test compound was investigated and established their maximum tolerated concentrations (MTC). For the first time, the ability to inhibit the reproduction of human poliomyelitis virus (vaccine strain Lsc2ab) for compounds № 10 (from the group of adamantyl-containing substances) and № 40 (with an alicyclic substituent in the alkoxy group) were determined: their chemotherapeutic index (CTI) values were 16 and 8 respectively. For the first time, the anti-influenza activity for the influenza virus of strain A / FV / 1/47 (H1N1) was detected for compounds № 5 (from the adamantyl group) and for compounds № 30 and № 33 (from the groups of cyclic and alicyclic substituents in the alkoxy group). The CTI of compound № 5 is 16, The СTI of compounds № 30 and № 33 was equal to 256, which is more than the reference drug rimantadine, СTI which was 172.2. The anti-influenza activity of these compounds was also confirmed in the in vivo experiments on the model of influenza pneumonia in mice. For the first time, the anti-herpetic effect of compound № 53 ((1- (2-methyl-3- butynoxy) -3- (2,2,6,6-tetramethyl piperidino) -2-propanol hydrochloride) was established: it inhibited the reproduction of herpes simplex virus (HSV / 1US) with an CTI 64. For the first time, the anti-hepatitis activity of compound № 50 (1-tert-butoxy-3- (2,2,6,6-tetramethyl-4-hydroxypiperidino) -2-propanol) was detected. The CTI of compound № 50 to the bovine viral diarrhea virus (BVDV), used as a test-model for the hepatitis C virus, was 32. The anti-hepatitis properties of this substance were also confirmed in an experimental hepatitis C virus production model (in transfection MT-4 cell cultures): it was show the dose depending action to the ability to produce RNA of HCV. The obtained experimental data indicate the prospect of further studies of the tested compounds in order to develop new antimicrobial and antiviral drugs based on them.