Cyanopyridines play a vital role owing to their range of biological and physiological activities. In the light of these biological activities and variety of industrial applications, some new of 6-Aryl-4-[4’-(p-chlorobenzyloxy)- 3’-methoxyphenyl]-2-methoxy-3-cyanopyridines (1a-l) & 6-Aryl-4-[4’-(p-chlorobenzyloxy)-3’- methoxyphenyl]-2-ethoxy-3-cyanopyridine (2a-l) have been prepared, by the cyclocondensation of 1-Aryl-3- [4’-(p-chlorobenzyloxy)-3’-methoxyphenyl]-propenones type (I) with malononitrile in presence of Sodiummethoxide & Sodiumethoxide. All the prepared compounds were characterized by their spectral (I.R.,
rature was maintained at 37 °C by a thermoregulated water circuit. The pH of the saturated solution was 7.4. Each strip was connected to a force transducer (FDT 10-A, May IOBS 99, COMMAT Iletisim Co., Ankara, Turkey) for measurement of the isometric force, which was continuously displaced and recorded on an online computer via a four-channel transducer data acquisition system (MP30B-CE, BIOPAC Systems Inc., Santa Barbara, CA) using software (BSL PRO v. 3.6.7, BIOPAC Systems Inc.) which also had the capacity to analyze the data. After mounting, each strip was allowed to equilibrate with a basal tension of 1 g for 60 min. Ca 2+ free KHS was replaced with fresh solution every 15 min during this time. N ω -nitro- L -
Chitosan is a polysaccharide usually obtained from deacetyla- tion of chitin, which after cellulose is the second most abundant natural biopolymer found in nature. It may be extracted from various sources, particularly from exoskeletons of arthropods of crustaceans, fungi, insects, annelids, mollusks and coelenter- ata. The structures of chitin and chitosan correspond to those of poly[␤(1→4)-2-acetamide-2-deoxy-d-glucopyranose] and poly[␤(1→4)-2-amino-2-deoxy-d-glucopyranose], respectively (Ravi Kumar 2000). The homopolymer is a weak base with a pK a value of the d -glucosamine residue of about 6.2–7.0 and is therefore insoluble at neutral and alkaline pH values. In acidic mediums, the amine groups will be positively charged, conferring to the polysaccharide a high charge density. Due to its polyca- tionic nature, chitosan, after being dissolved in aqueous acid solutions, can be easily molded and used as membranes, beads, microparticles and gels (Rinaudo 2006; Ravi Kumar 2000). Also, its functional properties such as biodegradability and low toxicity (Domard 2011; Kean and Thanou 2010) have driven the research
The discovery of novel active compounds with new mechanisms of action, higher efficacy and improved selectivity is a matter of urgency to multi drug resistance and toxicity problems associated with many therapeutic drugs . Great attention has been given to transition metal complexes and extensive biological effects have been found for many of them . One of the first therapeutic metallodrugs was salvarsan (-a), an arsenic-based antimicrobial agent developed by Paul Ehrlich for the treatment of syphilis. With the addition of mercury and bismuth, salvarsan remained the standard remedy for syphilis until it was replaced by penicillin after World War II. Salvarsan is regarded as the birth of modern chemotherapy and often cited as the beginning of modern research and development of metallodrugs. In 1965, the star of the field, the anticancer agent cisplatin, was discovered by Barnett Rosenberg and Loretta VanCamp at Michigan State University . This platinum-based (-b) anticancer drug has played a crucial role. Complexes with other metal ions like titanium and ruthenium are also being explored with some success but none is used in the clinic yet [2,4].
The in vitro antibacterial screening activityof parent acid and complexes 1-4 are given in Table 1. Inhibition zones with a diameter less than 10 mm are considered as weak; larger than 10 mm but less than 16 mm are considered as moderate and finally larger than 16 mm and above are active (Chohan et al., 2006). Complex 1 showed a significant result against all the tested bacterial strains even though the activities obtained were from weak to moderate activity. Meanwhile, complexes 2-4 were found to be significantly active against gram-positive bacterial strains. Against Bacillus subtillis and Staphylococcus aureus at 1.0 mg mL − 1 , the inhibition zones obtained for complex 4 were 18 and 19 mm respectively indicating that the in vitro antibacterial activity was in the active mode. Moreover, the inhibition zone diameters of complexes 1-3 in the range of 9-13 mm indicated that their activities were weak. Hence, complex 4 was more active compared to diorganotin(IV) complexes derivatives. In this study, the tin atom moiety of complex 4 is five-coordinated and exists in trans-R 3 SnO 2 geometry in solution form;
Synthesis - Lapachol was isolated from Tabebuia ochracea in a previous study by Zani et al. (1991). Thi- osemicarbazide (Sigma-Aldrich, Steinheim, Germany) was purified by crystallisation from water. Acetone (Vetec, RJ, Brazil), methanol (Sigma-Aldrich), semi- carbazide hydrochloride (Sigma-Aldrich) and sodium hydroxide (Sigma-Aldrich, Steinheim, Germany) were used without further purification. Column chromatogra- phy was performed using silica gel 60G (70-230 mesh). Thin-layer chromatography (TLC) was executed on pre- coated TLC silica gel 60F 254 plates Merck (Darmstadt, Germany) and the spots were visualised under ultravio- let (UV) light at wavelengths of 254 and 366 nm after the plates had been sprayed withvanillin-H 2 SO 4 and heated at 120ºC for 10 min. Analytical high-pressure liquid chromatography (Shim-Pak prep SiL, 4 µm, 4.6 x 250 mm, 1 mL/min) was performed on a Shimadzu chro- matography system equipped with an LC10AD pump and a UV detector set at λ 210 nm and λ 240 nm. Nuclear
Research in this area is still very active and is directed towards the synthesisof compounds with enhanced pharmacological activity. Generally, these com- pounds are synthesized by the condensation of o-phenylenediamines with α , β -un- saturated carbonyl compounds, 5 β -haloketones or ketones. 6 A variety of re-
different assay conditions and other bacterial strains were employed, which can explain the slight differences in the MIC obtained in this study. The peptide LyeTx I- K-HYNIC derivative (C-terminal modification) main- tained its antimicrobialactivity, exhibiting similar MIC for S. aureus and about two-fold higher MIC for E. coli, when compared to the non-modified peptide. On the other hand, the peptide HYNIC-LyeTx I derivative (N- terminal modification) did not inhibit bacterial growth (NI: no inhibition). Thus, the N-terminal modification suppressed the antimicrobialactivityof peptide HYNIC- LyeTx I derivative, suggesting that the N-terminal portion is important for the peptide interaction with bacteria. Therefore, only the peptide LyeTx I-K-HYNIC derivative was selected for further radiolabeling with 99m Tc, in order to be tested as a specific imaging probe for infectious.
Several new pryrazolo-pyridazine derivatives (4a-h) were synthesized through multi-step synthesisand evaluated for their antimicrobial activities. In the first step, 6-phenyl-2,3,4,5-tetrahydropyridazin-3-one (2) was prepared by reacting 4-(4-chlorophenyl)-4-oxobutanoic acid (1) with hydrazine hydrate. Then, aryl-aldehydes were reacted with 2 to furnish pyridazinone derivatives (3a-g). Finally, pyridazinones (3a-h) were reacted with hydrazine hydrate to furnish the title compounds (4a-h). The newly synthesized compounds were evaluated for their in vitro antibacterial and antifungal activities against six microbial strains. Compounds 4d, 4e and 4f exhibited significant antibacterial action, whereas compounds 4c and 4d showed potential antifungal activity. Compound 4d, 5-(4-Chlorophenyl)-3-(4-fluorophenyl)-3,3a,4,7-tetrahydro-2H-pyrazolo[3,4-c]pyridazine, emerged as lead compound having broad spectrum ofantimicrobial action.
Pseudomonas aeruginosa is an opportunistic microorganism with the ability to respond to a wide variety of environmental changes, exhibiting a high intrinsic resistance to a number ofantimicrobial agents. This low susceptibility to antimicrobial substances is primarily due to the low permeability of its outer membrane, efflux mechanisms and the synthesisof enzymes that promote the degradation of these drugs. Cephalosporins, particularty ceftazidime and cefepime are effective against P. aeruginosa, however, its increasing resistance has limited the usage of these antibiotics. Encapsulating antimicrobial drugs into unilamellar liposomes is an approach that has been investigated in order to overcome microorganism resistance. In this study, antimicrobialactivityof liposomal ceftazidime and cefepime against P. aeruginosa ATCC 27853 and P. aeruginosa SPM-1 was compared to that of the free drugs. Liposomal characterization included diameter, encapsulation efficiency and stability. Minimum Inhibitory Concentration (MIC) was determined for free and liposomal forms of both drugs. Minimum Bactericidal Concentration (MBC) was determined at concentrations 1, 2 and 4 times MIC. Average diameter of liposomes was 131.88 nm and encapsulation efficiency for cefepime and ceftazidime were 2.29% end 5.77%, respectively. Improved stability was obtained when liposome formulations were prepared with a 50% molar ratio for cholesterol in relation to the phospholipid. MIC for liposomal antibiotics for both drugs were 50% lower than that of the free drug, demonstrating that liposomal drug delivery systems may contribute to increase the antibacterial activityof these drugs.
The obtained data are presented in the Table I. The experiments indicated that all tested compounds 6a‒v showed more or less comparable activitywith reference drug against all bacteria species with inhibition zone 20‒24 mm. Eight compounds (6a, 6b, 6e, 6k, 6l, 6m, 6r and 6q) exhibited good activity against different bacterial species, the activityof the rest was moderate. A very promising antimicrobialactivity was shown by compounds 6k and 6l (Table I). Compound 6k is the most active against S. aureus, Sh. Dysenteriae Flexneri 6858 and E. coli showing inhibition zone almost equal to reference drug, while compound 6l was active only against S. aureus and E. coli. Compounds 6b, 6m and 6r also showed good activity against S. aureus with 23 mm inhibition zones. The same good activity possessed compound 6r against Sh.
Synthesisof N-nitroso-N-substituted glycines V a – c 20 : To a suspension of N-substituted glycine IV a–c (0.1 mole) in water (120 mL) at 0 ºC, a solution of sodium nitrite (6.9 g, 0.1 mole) in water (24 mL) was added drop wise. After 2 hours, the reaction mixture was filtered and acidified with concentrated hydrochloric acid. The precipitate so formed was collected by filtration, washed with cold water, dried in air and recrystallized from aqueous alcohol.
SYNTHESISAND EVALUATION OFANTIMICROBIALACTIVITYOF HALOGENATED FURANONES AND COMPOUNDS ANALOGUES TO NOSTOCLIDES. Considering the broad spectrum of biological activityof gamma-butyrolactone derivatives, we presented the synthesisof 3,4-dihalo-5-arylidenefuran-2(5H)-ones (17-21) and analogues (24-28) of the natural product nostoclide (7,8). Furanones 17-21 were synthesized from the condensation of aromatic aldehydes with lactones 14 and 15, that were obtained from mucobromic and mucochloric acids. Lactone 15 was converted into the intermediate 23 in 36% overall yield. Compound 23 was then transformed into the nostoclide analogues 24-28. Some of the compounds prepared showed antimicrobial activities against Escherichia coli, Staphylococcus aureus and Bacillus cereus comparable to commercial antibiotics.
In order to ind an antimicrobial agent, nine compounds were synthesized and tested against Gram-positive, Gram- negative, and alcohol acid resistant bacteria and yeast. All compounds were active against all Gram-positive bacteria. One of the compounds was the most active, inhibiting Gram- positive, Gram-negative, and alcohol acid resistant bacteria and also the yeast. he other compounds had varied activity between classes of Gram-positive and acid alcohol resistant bacteria. Compounds containing chlorine in the molecule showed the best antibacterial activity, thus demonstrating the power of this atom on the bacteria. he compounds with sub- stituents nitro and methyl also showed signiicant activity. All the compounds presented the � coniguration. he chemical structures of the compounds were determined by physical methods IR, 1 HNMR, 13 CNMR and mass spectrometry.
In the present study as in the part of medicinal chemistry programme, we have been synthesized a series of new sulfonamide derivatives, 9-(substitutedbenzenesulfonyl)-6-chloro-9H- purines and carbamate derivatives, 6-chloro-purine-9-carboxylicacid substituted alkyl/arylester by in situ fashion. Antimicrobialactivity against three bacterial strains and three fungal strains at two different concentrations, 100 and 200 µg/mL including MIC values was investigated. Bio-screening data disclosed that all the title compounds exhibited promising antimicrobialactivity at both the concentrations. Sulfonamide derivatives 7a, 7c and 7d, and one carbamate derivative 9a showed promising growth of inhibition of selected bacterial and fungal strains and these compounds showed MIC values in the range of 18.0- 25.0 µg/mL as compared with other title compounds and near activityof the standards. In whole comparison, the sulfonamide derivativesof 6-chloropurine are acted as potential antimicrobial agents than that of carbamate derivatives. The study of results encouraged us to design new library of purine derivatives as antimicrobial agents in future endeavors and might be worthy to medicinal chemistry.
A mixture of 4-piperidone hydrochloride monohydrate (1, 10 mmol) and various substituted aromatic aldehydes (20 mmol) in ethanol (10 mL) was stirred at room temperature (29 °C) for 10 min. The reaction mixture was cooled to 0 °C and conc. HCl (2.0 g, 20 mmol) was added dropwise. The resulting mixture was refluxed for about 4.5 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the crude product was filtered and recrystallized from ethanol to obtain pure 3a, 3b, 3d and 3f of this series in excel- lent yields. The compounds 3c and 3e were neutralized with 10 % NaOH (8 mL), extracted twice with chloroform (2×50 mL) and dried over by sodium sulphate. The combined organic layer was concentrated under reduced pressure and the crude product was purified by column chromatography using a 5 % mixture of methanol and chloroform as the eluent to obtain pure compounds 3c and 3e. Detailed structures for corresponding reactants and products are shown in Table I.
membered chelate rings around the copper atom in a trans-N 2 O 2 environment; spectroscopic data confirm that the other complexes exhibit similar molecular arrangement. The antimicrobialactivityof all compounds has been tested on seven different strains of bacteria: Bacillus cereus, Bacillus subtilis, Escherichia coli, Enterococcus faecalis, Klebsiella pneumoniae, Pseudomonas aeruginosa and Staphylococcus aureus. In general, Mannich bases were more active than complexes, HL11 (R 1 = OH; R 2 =H; R 3 = Me; R 4 = Bn) and HL13 (R 1 = OH; R 2 = H; R 3 = Br; R 4 = Bn) being
The cytotoxic effects of the synthesized compounds were evaluated against the following human cancer cell lines and non-tumor cells (PBMC), all transformed cell lines were obtained from the National Cancer Institute, Bethesda, MD, USA: PC-3M (prostate carcinoma), OVCAR-8 (ovarian carcinoma) and NCI-H358M (bronchoalveolar lung carcinoma). The cell lines were maintained in RPMI-1640 medium (cancer cells) supplemented with 10% fetal bovine serum, 2 mmol L -1 glutamine, 100 µg mL -1 penicillin and
In conclusion, the second-generation of P-gp modulators have a better pharmacologic profile than the first-generation, but they also retain some characteristics that limit their use as P-gp modulators. In particular, these compounds significantly inhibit the metabolism and excretion of cytotoxic agents, thus leading to unacceptable toxicity which requires chemotherapy dose reductions. Several of the second- generation P-gp modulators, including valspodar (100) and biricodar (101), are substrates for cytochrome P450. Therefore, the competition between chemotherapeutic agents and these P-gp modulators for cytochrome P450 activity has given rise to unpredictable pharmacokinetic interactions . Moreover, since the pharmacokinetic interactions between P-gp inhibitors and cytotoxic agents are unpredictable and cannot be determined in advance, reducing the dose of a cytotoxic agent may result in underdosing, thus limiting the use of these second-generation modulators in the treatment of MDR cancers . Many second-generation modulators may also inhibit other transporters, particularly those of the ABC transporter family. This can lead to a decreased capacity of normal cells to extrude toxic compounds or xenobiotics in the liver, kidney, or gastrointestinal tract [353, 354]. The endothelial distribution of P-gp and other ABC transporters indicates that they are involved in physiological roles such as the regulation of the entry of certain molecules into the CNS and other anatomic compartments, such as the testis and placenta . Therefore, the inhibition of transporters other than P-gp, for example, the ABC transporter BCRP, a functional regulator of hematopoietic stem cells, may lead to serious adverse effects including neutropenia and other myelotoxic effects . In an effort to alleviate these problems, investigators and industry have started to focus on a new generation of P-gp inhibitors, the third generation.
Bruker AM-400 spectrometer (400 MHz). The 1 H NMR internal standard used was tetramethylsilane (TMS). Chromatographic separations were performed on a silica gel column by gravity chromatography (Kieselgel 40, 0.01–0.04 mm; Merck). Yields are given after purification, unless otherwise stated. Where analyses are indicated by symbols, the analytical results are within 61% of the theoretical values. All spectral and elemental analysis data (shown in the Supporting Information) were in agreement with the assigned structures. All compounds were estimated to be .95% pure according to analytical reversed-phase high performance liquid chromatography (RP-HPLC) and detection with MS (see Supporting Information for details) for details. No UV-active impurities were observed with analytical RP-HPLC and UV detection at 245 nm. The data for 16c was displayed as represented in Figure 2.