Ciprofloxacin is a widely used fluoroquinolone antibiotic. In this work, a comprehensive evaluation of MP2 and DFT with different functionals and basis sets was carried out to select the most suitable level of theory for the study of the NMR properties of ciprofloxacin. Their relative predictive capabilities were evaluated comparing the theoretically predicted and experimental spectral data. Our computational results indicated that in contrast to the solid state, the molecule of ciprofloxacin does not exist as a zwitterion in gaseous state. The results of the calculations of the chemical shifts most close to the experimental were obtained with B3LYP/aug‐cc‐pVDZ. The F–C coupling constants were calculated systematically with different DFT methods and several basis sets. In general, the calculations of the coupling constants with the BHandH computational method including the applied in this work 6‐311++G**, EPRII, and EPRIII basis sets showed a good reproducibility of the experimental values of the coupling constants.

Herein we report the synthesis of different derivatives of (fluoro)quinolones norfloxacin, ciprofloxacin and pipemidic acid, by incorporating (benzoylamino)methyl on the free nitrogen of the pyperazinyl moiety. The compounds were structurally characterized by 1D and 2D NMR, FTIR and highresolution mass spectroscopy. In addition, their physicochemical properties were a matter of interest to be correlated with their structure and antimicrobial activity in vitro. Their antimicrobial activities were screened against Gram-positive, Gram-negative bacteria and C. albicans. Higher distribution coefficients and consequently lower water solubility were determined for all synthesized compounds than the ones of the corresponding leading compounds. Inconsequential correlations between the lipophilicity of the compounds and MIC were observed, suggesting that passive diffusion is not the only mechanism for their penetration into bacterial cells. Further studies are needed to determine how substitutions in the (fluoro)quinolone moiety affect the primary target(s), substrate behavior in respect to bacterial transporters and overall bioavailability.Keywords: (benzoylamino)methyl; quinolones; structure; physicochemical properties; antimicrobial activity СИНТЕЗА, ФИЗИЧКОХЕМИСКА КАРАКТЕРИЗАЦИЈА И АНТИБАКТЕРИСКА АКТИВНОСТ НА НОВИ (БЕНЗОИЛАМИНО)МЕТИЛНИ ДЕРИВАТИ НА ХИНОЛОНИВо трудот е прикажана синтеза на различни деривати на (флуоро)хинолони со инкорпорирање на (бензоиламино)метилна група на слободниот азот од пиперазинскиот фрагмент кај норфлоксацинот, ципрофлоксацинот и пипемидинската киселина како водечки соединенија. Синтетизираните соединенија беа структурно карактеризирани со помош на 1D и 2D NMR, FTIR и масена спектрометрија со висока резолуција. Дополнително беа определени физичкохемиските особини на новосинтетизираните соединенија и корелирани со нивната структура и антимикро- 179-197 (2016) 180 бната активност in vitro. Антимикробната активност на новите соединенија беше испитувана на Gram-позитивни и Gram-негативни бактерии и на C. albicans. Сите новосинтетизирани соеди-ненија покажаа повисок коефициент на распределба и соодветно пониска растворливост во вода во однос на водечките соединенија. Корелациите меѓу липофилноста на синтетизираните соединенија и минималната инхибиторна концентрација (MIC) не беа статистички значајни, што укажува на тоа дека пасивната дифузија не е единствениот механизам со кој тие пенетрираат во бактериските клетки. Потребни се понатамошни истражувања за да се испита како супституциите во (флуоро)хинолонското јадро влијаат врз примарната цел(и), супстратното однесување во однос на бактериските транспортери и севкупната биорасположливост.

We report the synthesis of [(3-chlorobenzamido)methyl]triethylammonium chloride in a reaction of N-(chloromethyl)-3-chlorobenzamide and triethylamine in dry acetone. The structure of the newly synthesized compound was characterized with 1H-NMR, 13C-NMR, FTIR and Mass spectroscopy.

Possible synergistic effect of tamoxifen (2 μM) and hydrazinyldiene-chroman-2,4-diones (10-100 μM) was examined with an aim to create more effective treatment for ER+ breast cancer. Anti-breast cancer effect has been evaluated on the proliferation of MCF-7 breast adenocarcinoma cells using MTT and alamarBlue assays. Cell viability was evaluated after 48h-treatment and the ICs50 of the coumarin derivatives were determined. The apoptotic effect was evaluated by detection of PARP cleavage and reduced activity of the survival kinase Akt. The results demonstrated dose-dependent activity, with a percent of growth inhibition after combination treatment being significantly higher (53% to 79%, 10 μM and 100 μM, respectively) than the one in the cell lines treated with tamoxifen (29% to 37%) and the synthesized coumarin derivatives alone (11% to 68%, 10 μM and 100 μM, respectively). The ICs50 of the synthesized compounds significantly decreased in synergy with tamoxifen (33% to 51%). Coumarin derivative having thiazole moiety with additional methyl groups attached to the carbons at positions 5 and 4 in the thiazole ring showed to be the most potent, with IC50 20 µM when administered alone and 10 µM in synergy with tamoxifen. The levels of phospho-Thr308 Akt were down-regulated by the combination treatment, pointing to tyrosine kinase phosphorylation inhibition. In conclusion, the novel coumarin derivatives enhance the activity of tamoxifen and this combination may be suitable for prevention of ER+ breast cancer or development of related compounds. Further studies are needed to elucidate precisely the type of receptor involved in the activity and the mechanism of action.