Marijan Kočevar

New fluorine-containing hydrazones active against MDR-tuberculosis

Several new fluorine-containing hydrazones were synthesized and screened for their in vitro antimycobacterial activity. Nine of these derivatives have shown a remarkable activity against MDR-TB strain with MIC 0.5 μg/mL and high value of selectivity index (SI). Compound 3h with the highest SI (1268.58) was used for stability evaluation with putative metabolites (ciprofloxacin and formylciprofloxacin) detection. Compound 3h was stable at pH 7.4 of aqueous buffer and rat plasma, in acidic buffers (at pH 3 and 5) slow decomposition was observed. Interestingly, no formylciprofloxacin was detected in the solution, and only slightly increased concentration of ciprofloxacin was observed instead. Trifluoromethyl hydrazones 3f and 3g exhibited the best activity also against two strains of Mycobacterium kansasii (MIC 1-4 μmol/L). All evaluated compounds were found to be non-cytotoxic.

A simple and general one-pot synthesis of some 2h-pyran-2-ones and fused pyran-2-ones

Abstract A general one-pot synthesis of some 2H-pyran-2-ones and fused pyran-2-ones starting from 1,3-dlcarbonyl compounds, N-acylglycines and one-carbon synthons (trialkyl orthoformates, diethoxymethyl acetate or N,N-dlmethylformamide dimethyl acetal) in acetic anhydride (or in a mixture of acetic anhydride and acetic acid) is described.

Pyrazolone-fused combretastatins and their precursors: synthesis, cytotoxicity, antitubulin activity and molecular modeling studies

A series of pyrazolone-fused combretastatins and precursors were synthesized and their cytotoxicity as well as antitubulin potential was evaluated. The hydrazide 9f and the pyrazolone-fused combretastatins 12a, 12b and 12c were highly cytotoxic against various tumor cell lines including cisplatin resistant cells. The same compounds were also the best inhibitors of tubulin polymerization. Molecular modeling results showed that they bind the colchicine binding site at the tubulin heterodimer. The hydrazide 9f arrested HeLa cells in the G2/M phase of the cell cycle and strongly affected cell shape and microtubule network.

New series of isoniazid hydrazones linked with electron-withdrawing substituents.

A series of new isoniazid hydrazones was synthesized by two procedures. In the first isoniazid was activated with diethoxymethyl acetate and condensed with the appropriate anilines. Alternatively, substituted anilines were activated by diethoxymethyl acetate and subsequently condensed with isoniazid. NMR study confirmed that both synthetic approaches gave the same tautomer. All compounds were screened for in vitro antimycobacterial activity. Most of them exhibited the same activity against Mycobacterium tuberculosis (MIC 1 μmol L(-1)) as isoniazid (INH), better activity against Mycobacterium kansasii 325/80 (MIC 0.125-0.250 μmol L(-1)), high value of selectivity index (SI) and IC(50) between 0.0218 and 0.326 mmol L(-1). Compound 2o with the best SI was used as a model compound for the stability test and was found to be stable at neutral pH, but under acidic conditions it slowly hydrolysed.

An “One-Pot” Synthesis of Substituted 3-Benzoylamino-5-oxo-5, 6, 7, 8-Tetrahydrocoumarins

Abstract A new simple “one-pot” synthesis of some 3-benzoylamino-5-oxo-5, 6, 7, 8-tetrahydrocoumarins from 1, 3-cyclohexanediones, hippuric acid, acetic anhydride and triethyl orthoformate or other one-carbon synthetic equivalent is described.

4-Ethoxymethylene-2-phenyl-5(4H)-oxazolene as a Synthon for the synthesis of Some 2H-Pyran-2-ones

Treatment of 4-ethoxymethylene-2-phenyl-5(4H)-oxazolone with activated methylene compounds under acidic or basic conditions leads to 2H-pyran-2-ones and fused pyran-2-ones. On the other hand, methyl (3-benzoylamino-5-methoxycarbonyl-2-oxo-2H-pyran-6-yl)-acetate (4) has also been prepared by a one-pot synthesis from dimethyl 1,3-acetonedicarboxylate, diethoxymethyl acetate, hippuric acid and acetic anhydride

ZrCl4-promoted halogen migration during an electrophilic amination of halogenated phenolsElectronic supplementary information (ESI) available: spectroscopic data (1H NMR,13C NMR, IR, MS), mp and elemental analysis (or HRMS) for the products 3 and 4. See http://www.rsc.org/suppdata/cc/b2/b203622c/Dedicated to Professor Waldemar Adam, University of Würzburg, Germany, on the occasion of his 65th birthday.

An electrophilic amination of halogenated phenols with diisopropyl diazenedicarboxylate in the presence of ZrCl4 as a Lewis acid, accompanied by a halogen migration, was demonstrated for the first time; the fluorine, chlorine, bromine, or iodine atom migrated during the amination process under mild reaction conditions.

Ceric(IV) ammonium nitrate in the selective conversion of hydrazides to esters

Abstract Hydrazides were treated with ceric(IV) ammonium nitrate (CAN) in the presence of the appropriate alcohol as a nucleophile to afford esters in good yields. Reactions took place exclusively at the hydrazino moiety even when other sensitive groups were present in either of the partners.

Pyrano [3,2-c]azepine, a new heterocyclic system. A new approach to pyrido [3,2-c]azepines

3-Benzoylamino-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydrocoumarin (1a) was used as a synthon in the preparation of the first derivatives of the pyrano[3,2-c]azepine system 2 and in two approaches to pyrido[3,2-c]azepines 4

CARBOXAMIDE OXIMES AS CONVENIENT PRECURSORS FOR THE SYNTHESIS OF PYRIMIDINE N-OXIDES

A general method for the synthesis of pyrimidine N-oxides from the appropriate carboxamide oximes is described. The conversion involves a treatment of various carboxamide oximes with either 1,1,3,3-tetramethoxypropane, 2,4-pentanedione, 3-ethoxy-2-propenal, 4,4-dimethoxy-2-butanone or 4-methoxy-3-butene-2-one in the presence of trifluoroacetic acid as a catalyst. The application of an unsymmetrical dicarbonyl compound leads exclusively to one product. Our approach is a method of choice for the preparation of pyridylpyrimidine N-oxides.