[Show abstract][Hide abstract] ABSTRACT: New quaternary ammonium salt-type compounds with lipophilic cholesterol and terpene moieties were synthesized. The compounds showed promising antibacterial and antimycobacterial activities. Those compounds containing the cholesterol moiety showed significant activity against Staphylococcus aureus, Staphylococcus epidermidis, and Enterococcus faecium. On the contrary, the antimycobacterial activity increased with the presence of the terpene unit in the molecule.
Archiv der Pharmazie 03/2014; · 1.54 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A series of heterocyclic derivatives analogous to (-)vasicinone, in which the vasicinone C-ring was replaced with alkyl chain terminated by tertiary amine was prepared. N3, C4-O, C4-S or C4-N were used as the sites of attachment. The 4-[3-(1-piperidyl)propylsulfanyl]derivatives displayed bronchodilatory effect at low micromolar concentrations on isolated rat trachea, and low toxicity both on Balb/c 3T3 mouse fibroblast cells and in mice.
European Journal of Medicinal Chemistry 01/2014; 74C:65-72. · 3.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The bulbs of Zephyranthes robusta (Amaryllidaceae) have been extensively analyzed for their chemical constituents, resulting in the isolation of 13 alkaloids. The chemical structures of the isolated compounds were elucidated by mass-spectrometric, and 1D- and 2D-NMR spectroscopic experiments. The complete NMR assignments were achieved for hippeastidine. All isolated alkaloids were evaluated for their erythrocytic acetylcholinesterase and serum butyrylcholinesterase inhibitory activities using the Ellman's method. Significant acetylcholinesterase inhibition activity was exhibited by 8-O-demethylmaritidine (IC50 (HuAChE) 28.0±0.9 μM).
[Show abstract][Hide abstract] ABSTRACT: To develop new potential antimycobacterial drugs, a series of pyrazinamide derivatives was designed, synthesized and tested for their ability to inhibit the growth of selected mycobacterial strains (Mycobacterium tuberculosis H37Rv, Mycobacterium kansasii and two strains of Mycobacterium avium). This Letter is focused on binuclear pyrazinamide analogues containing the -CONH-CH2- bridge, namely on N-benzyl-5-chloropyrazine-2-carboxamides with various substituents on the phenyl ring and their comparison with some analogously substituted 5-chloro-N-phenylpyrazine-2-carboxamides. Compounds from the N-benzyl series exerted lower antimycobacterial activity against M. tuberculosis H37Rv then corresponding anilides, however comparable with pyrazinamide (12.5-25μg/mL). Remarkably, 5-chloro-N-(4-methylbenzyl)pyrazine-2-carboxamide (8, MIC=3.13μg/mL) and 5-chloro-N-(2-chlorobenzyl)pyrazine-2-carboxamide (1, MIC=6.25μg/mL) were active against M. kansasii, which is naturally unsusceptible to PZA. Basic structure-activity relationships are presented.
[Show abstract][Hide abstract] ABSTRACT: Nabumetone is a non-acidic, nonsteroidal anti-inflammatory prodrug. Following oral administration, the prodrug is converted in the liver to 6-methoxy-2-naphthylacetic acid (6-MNA), which was found to be the principal metabolite responsible for the NSAID effect. The pathway of nabumetone transformation to 6-MNA has not been clarified, with no intermediates between nabumetone and 6-MNA having been identified to date. In this study, a new, as yet unreported phase I metabolite was discovered within the evaluation of nabumetone metabolism by human and rat liver microsomal fractions. Extracts from the biomatrices were subjected to chiral LLE-HPLC-PDA and achiral LLE-UHPLC-MS/MS analyses to elucidate the chemical structure of this metabolite. UHPLC-MS/MS experiments detected the presence of a structure corresponding to elemental composition C15H16O3, which was tentatively assigned as a hydroxylated nabumetone. Identical nabumetone and HO-nabumetone UV spectra obtained from the PDA detector ruled out the presence of the hydroxy group in the aromatic moiety of nabumetone. Hence, the most likely structure of the new metabolite was 4-(6-methoxy-2-naphthyl)-3-hydroxybutan-2-one (3-hydroxy nabumetone). To confirm this structure, the standard of this nabumetone metabolite was synthesized, its spectral (UV, CD, NMR, MS/MS) and retention properties on chiral and achiral chromatographic columns were evaluated and compared with those of the authentic nabumetone metabolite. To elucidate the subsequent biotransformation of 3-hydroxy nabumetone, the compound was used as a substrate in incubation with human and rat liver microsomal fraction. A number of 3-hydroxy nabumetone metabolites (products of conjugation with glucuronic acid, O-desmethylation, carbonyl reduction and their combination) were discovered in the extracts from the incubated microsomes using LLE-HPLC-PDA-MS/MS experiments. On the other hand, when 3-hydroxy nabumetone was incubated with isolated rat hepatocytes, 6-MNA was detected as the principal metabolite of 3-hydroxy nabumetone. Hence, 3-hydroxy nabumetone could be the missing link in nabumetone biotransformation to 6-MNA (i.e. nabumetone→3-hydroxy nabumetone→6-MNA).
Journal of pharmaceutical and biomedical analysis 03/2013; 80C:164-172. · 2.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Contrary to a number of reports, alkylations of the privileged 3,4-dihydroquinazoline scaffold provide N3-alkylated products, and not 4-alkoxyquinazolines. To correctly assign the structure, 13C NMR shifts of the –Z–CHn– (Z=O, N) fragment are necessary; resonances in the 45–55 ppm range are indicative of N3-alkylation. Treatment of 3,4-dihydroquinazoline-4-one with p-TsCl afforded the N3-tosylated compound, whose reaction with an amine yielded the corresponding N3-alkyl derivative. A mechanism corroborated by 15N-labeling involving pyrimidine ring opening and recyclisation is proposed. Finally, the unambiguous preparation of 4-alkoxyquinazolines is described via treatment of 3,4-dihydroquinazoline-4-ones with PCl5 followed by an alkoxide.
[Show abstract][Hide abstract] ABSTRACT: 5-Chloropyrazinamide (5-Cl-PZA) is an inhibitor of mycobacterial fatty acid synthase I with a broad spectrum of antimycobacterial activity in vitro. Some N-phenylpyrazine-2-carboxamides with different substituents on both the pyrazine and phenyl core possess significant in vitro activity against Mycobacterium tuberculosis. To test the activity of structures combining both the 5-Cl-PZA and anilide motifs a series of thirty 5-chloro-N-phenylpyrazine-2-carboxamides with various substituents R on the phenyl ring were synthesized and screened against M. tuberculosis H37Rv, M. kansasii and two strains of M. avium. Most of the compounds exerted activity against M. tuberculosis H37Rv in the range of MIC = 1.56-6.25 µg/mL and only three derivatives were inactive. The phenyl part of the molecule tolerated many different substituents while maintaining the activity. In vitro cytotoxicity was decreased in compounds with hydroxyl substituents, preferably combined with other hydrophilic substituents. 5-Chloro-N-(5-chloro-2-hydroxyphenyl)pyrazine-2-carboxamide (21) inhibited all of the tested strains (MIC = 1.56 µg/mL for M. tuberculosis; 12.5 µg/mL for other strains). 4-(5-Chloropyrazine-2-carboxamido)-2-hydroxybenzoic acid (30) preserved good activity (MIC = 3.13 µg/mL M. tuberculosis) and was rated as non-toxic in two in vitro models (Chinese hamster ovary and renal cell adenocarcinoma cell lines; SI = 47 and 35, respectively).
[Show abstract][Hide abstract] ABSTRACT: A series of pyrazinamide derivatives with alkylamino substitution was designed, synthesized and tested for their ability to inhibit the growth of selected mycobacterial, bacterial and fungal strains. The target structures were prepared from the corresponding 5-chloro (1) or 6-chloropyrazine-2-carboxamide (2) by nucleophilic substitution of chlorine by various non-aromatic amines (alkylamines). To determine the influence of alkyl substitution, corresponding amino derivatives (1a, 2a) and compounds with phenylalkylamino substitution were prepared. Some of the compounds exerted antimycobacterial activity against Mycobacterium tuberculosis H37Rv significantly better than standard pyrazinamide and corresponding starting compounds (1 and 2). Basic structure-activity relationships are presented. Only weak antibacterial and no antifungal activity was detected.
[Show abstract][Hide abstract] ABSTRACT: A series of 19 new compounds related to pyrazinamide were synthesized, characterized with analytical data and screened for in vitro whole cell antimycobacterial activity against Mycobacterium tuberculosis H37Rv, Mycobacterium kansasii and two types of Mycobacterium avium. The series consisted of 3-(benzylamino)-5-cyanopyrazine-2-carboxamides and 3-(benzylamino)pyrazine-2,5-dicarbonitriles with various substituents on the phenyl ring. RP-HPLC method was used to determine the lipophilicity of the prepared compounds. Nine compounds exerted similar or better activity against Mycobacterium tuberculosis compared to pyrazinamide (MIC=6.25-12.5μg/mL). 3-(Benzylamino)pyrazine-2,5-dicarbonitrile inhibited all of the tested mycobacterial strains with MIC within the range 12.5-25μg/mL. Although not the most active, 4-NH(2) substituted compounds possessed the lowest in vitro cytotoxicity (hepatotoxicity), leading to selectivity index SI=5.5 and SI >21.
[Show abstract][Hide abstract] ABSTRACT: The presented work deals with synthesis and isolation of constitutional isomers of triazolo-fused azaphthalocyanines. Distribution of the isomers did not follow the statistical calculations due to steric effects of the substituents preferring the least sterically stressed C(4h) isomer.
Chemical Communications 03/2012; 48(36):4326-8. · 6.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A series of 14 new compounds related to pyrazinamide were synthesized, characterized with analytical data and screened for in vitro antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium kansasii and two types of Mycobacterium avium. The series comprised of N-substituted 3-aminopyrazine-2,5-dicarbonitriles derived from 3-chloropyrazine-2,5-dicarbonitrile by nucleophilic substitution of chlorine by various non-aromatic amines (alkylamines, cycloalkylamines and heterocyclic amines). Noteworthy antimycobacterial activity against M. tuberculosis was found among the alkylamino derivatives, for example, 3-(heptylamino)pyrazine-2,5-dicarbonitrile inhibited M. tuberculosis at MIC=51 μmol/L. 3-(Hexylamino)pyrazine-2,5-dicarbonitrile inhibited M. kansasii at MIC=218 μmol/L. Basic structure-activity relationships are discussed. A comparison between calculated and experimentally determined lipophilicity parameters within the series is included.
[Show abstract][Hide abstract] ABSTRACT: Antimycobacterial activity of phenyl salicylates (salols) was studied in connection with antituberculotic activity of salicylic derivatives. Phenyl salicylates are esters. Our attention was previously oriented on amides. Phenyl salicylates (salols) represent a new group of antimycobacterial compounds. They are less active than the corresponding amides. The most active compound in the group under study is substituted on phenyl in the salicyl moiety with a 4-methoxy group. The study reports a new item of information about antimycobacterial salicylic derivatives. Keywords: salols mycobacterium antimycobacterial activity phenyl salicylate.
Ceská a Slovenská farmacie: casopis Ceské farmaceutické spolecnosti a Slovenské farmaceutické spolecnosti 01/2012; 61(6):282-284.
[Show abstract][Hide abstract] ABSTRACT: Dihydropyrans have been prepared by the cyclisation of easily accessible propargyl vinyl ethers with (TFP)AuCl/AgBF(4) as a catalyst in high yields. These compounds undergo acid-catalysed rearrangement into cyclopentenone derivatives.
Chemical Communications 09/2011; 47(33):9390-2. · 6.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A series of simple desmethoxy analogues of coruscanone A was prepared via a novel version of Ti(iPrO)(4)-mediated Knoevenagel condensation of cyclopentenedione with substituted benzaldehydes and cinnamic aldehydes, and the compounds were evaluated for antifungal activity and cytotoxicity. The most potent 2-benzylidenecyclopent-4-ene-1,3-dione possessed antifungal effect comparable to coruscanone A and a somewhat broader spectrum of activity against Candida species. The compound was also superior to fluconazole against several non-albicans Candida sp. Evaluation of the ability of the compound to influence cell proliferation using two different assays showed that 2-benzylidenecyclopent-4-ene-1,3-dione has lower cytotoxicity compared to the natural product.
[Show abstract][Hide abstract] ABSTRACT: A series of forty-five derivatives of 3-phenyl-4-thioxo-2H-1,3-benzoxazine-2(3H)-ones and forty-five derivatives of 3-phenyl-2H-1,3-benzoxazine-2,4(3H)-dithiones was synthesised. The compounds exhibited in-vitro activity against Mycobacterium tuberculosis, M. kansasii (two strains), and M. avium. The most active derivatives were more active than isonicotinhydrazide (INH). The quantitative relationships between the
structure and antimycobacterial activity were calculated. The activity against M. tuberculosis increased with the lipophilicity of the substituents.
Chemical Papers- Slovak Academy of Sciences 06/2011; 65(3):352-366. · 1.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A novel capillary electrophoretic method for the separation of pancuronium (PM) and vecuronium (VM) ions utilizing capacitively coupled contactless conductivity detection was devised and validated. The separation was carried out in bare fused-silica capillaries (50 μm id, 75/45 cm) at 25°C. Optimal BGE was 50 mM borate buffer of pH 9.5 containing 12.5 mg/mL of (2-hydoxypropyl)-γ-CD. The samples were injected hydrodynamically at 1000 mbar for 3 s. Separation was performed at +30 kV. Under such conditions the PM and VM were base-line resolved and the separation took < 4 min. For quantification phenyltrimethylammonium iodide was used as internal standard. Calibration curves were linear for both pancuronium bromide (PMB) and vecuronium bromide (VMB) in the range 25-250 μg/mL with r> 0.9968. The limits of detection were 7 and 6 μg/mL for PMB and VMB, respectively. The accuracy tested by recovery experiment at three concentration levels of added PMB and VMB was satisfactory (95.7-102.7%, n =3, with RSD < 2.61%). The method was successfully applied to the assay of PMB and VMB in commercial injection solutions.
[Show abstract][Hide abstract] ABSTRACT: New 3-(4-alkylphenyl)-4-thioxo-2H-1,3-benzoxazine-2(3H)-ones and 3-(4-alkylphenyl)-2H-1,3-benzoxazine-2,4(3H)-dithiones were synthesized. The compounds were tested for in vitro antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium avium and two strains of Mycobacterium kansasii. The antimycobacterial activity increased with the replacement of the carbonyl group by the thiocarbonyl group in the starting 3-(4-alkylphenyl)-2H-1,3-benzoxazine-2,4(3H)-diones. The most active derivatives were more active than isonicotinhydrazide (INH). Free-Wilson analysis was also carried out and the activity contribution was examined.