Synthesis of (+/-)Abyssinone I and related compounds: Their anti-oxidant and cytotoxic activities

An efficient and facile synthesis of naturally occurring prenylated flavonoids and their analogs have been described. Abyssinone I (9a) was prepared by condensing 2,2-dimethyl chrom-3-en-6-carboxaldehyde (5a) with protected resacetophenone under phase transfer conditions followed by deprotection and cyclization. The influence of prenyl group on anti-oxidant and cytotoxic activities was studied. The presence of 3'-prenyl group as in 8c enhanced radical scavenging activity but decreased reducing power activity when compared to non-prenylated analog 8f. In vitro testing in MCF-7 cell line revealed that prenylated chalcones and flavanones showed better inhibitory activity than their non-prenylated counterparts. Abyssinone I and its chalcone though exhibited negligible anti-oxidant activity their cytotoxic activities were comparable with other prenylated analogs.     

Structure-activity relationships of novel heteroaryl-acrylonitriles as cytotoxic and antibacterial agents

Eighteen new 2,6-disubstituted acrylonitriles and two new (benzimidazol-1-yl)-acetamide derivatives were prepared and screened for antibacterial and cytotoxic activities on 12 human cancer cell lines. Based on the lead structure 2-(benzimidazol-2-yl)-3-(5-nitrothiophen-2-yl) acrylonitrile it was found that placement of methyl groups at the 5,6 positions of the benzimidazole ring lead to a 3-fold increase in overall cytotoxic activity. Replacing the nitrothiophene for pyridine reduced cytotoxic activity as did replacing the nitro group for a methoxy group. Cytotoxic activity was only slightly reduced when the benzimidazole ring was replaced by a imidazo[4,5-b]pyridine or a benzthiazole ring but replacement by benzoxazole led to a substantial decrease in activity. Moving the acrylonitrile group from position 2 to position 1 of the benzimidazole ring also resulted in moderately active compounds. (Benzimidazol-1-yl)acetamides showed only modest activity. The structure-activity relationships found in the cytotoxicity studies are mirrored in the results of the antibacterial experiments.     

Amide isosteres in structure-activity studies of antibacterial minor groove binders

Antibacterial minor groove binders related to the natural product, distamycin, are development candidates for novel antibiotics. Alkenes have been found to be effective substitutes for the isosteric amide links in some positions and alkyl groups larger than methyl have been found to increase binding to DNA in both selectivity and affinity. However the impact of other isosteres such as diazenes and the position of an alkyl group with respect to DNA binding and antibacterial activity are not known. The effects of some systematic variations in the structure of polyamide minor groove binders are investigated. Isosteres of the amide link (alkenes and diazenes) are compared: it is shown that all three are competent for binding to DNA but that alkene links give the tightest binding and highest antibacterial activity; no significant antibacterial activity was found for compounds with a diazene link. Within a series of alkene linked compounds, the effect of branched N-alkyl substituents on binding to DNA and antibacterial activity is investigated: it was found that C3 and C4 branched chains are acceptable at the central pyrrole residue but that at the pyrrole ring adjacent to the basic tail group, a C4 branched chain was too large both for DNA binding and for antibacterial activity. The active branched alkyl chain compounds were found to be especially active against Mycobacterium aurum, a bacterium related to the causative agent of tuberculosis.     

A quantitative structure-activity relationship study on a novel class of calcium-entry blockers: 1-[(4-(aminoalkoxy)phenyl)sulphonyl]indolizines

A quantitative structure-activity relationship (QSAR) study has been made on two different series of 1-[(4-(aminoalkoxy)phenyl)sulphonyl]indolizines acting as calcium entry blockers, using some physicochemical and structural parameters. Two different assays were reported for both the series: (IC(50))(A), referring to the molar concentration of the compound required to reduce [3H] nitrendipine binding by 50%, and (IC(50))(B), referring to that required to block Ca(2+) induced concentration of K(+) depolarised rat aorta by 50%. For series 1, where the 2-position substituents of indolizine ring were varied along with the aminoalkoxy moieties of the phenyl ring, the QSAR analysis shows that the 2-position substituents can equally affect both the activities through their hydrophobic and electronic properties and the aminoalkoxy moiety through some steric effects. For series 2, where the indolizine ring has been replaced by varying heterocyclic rings, along with the changes in aminoalkoxy moiety of the phenyl ring, the QSAR exhibits that these different heterocyclic rings affect both the activities through some steric roles, altering the conformations of the receptors from system A to system B. Among the different heterocyclic rings, the N-substituted indole ring is shown to be more conducive to both the activities than any other ring. However, a 5-membered ring is indicated to be less effective than a 9- or 10-membered ring for activity B. Additionally, the amino moieties having phenyl ring with methoxy groups at 3,4,and 5-positions are shown to favour both A and B activities.     

Synthesis of new series of 1-Aryl-1,4-dihydro-4-oxo-6-methyl pyridazine-3-carboxylic acid as potential antibacterial agents

New series of 1-aryl-1,4-dihydro-4-oxo-6-methyl pyridazine-3-carboxylic acid has been synthesized and the structures of the new compounds were established on the basis of 1H-NMR, mass (ES/MS), elemental analysis and IR spectral data. In vitro antibacterial activity (MIC activity) was evaluated and compared with standard drugs ciprofloxacin, sparfloxacin and trovafloxacin. Most of the compounds in the series have shown very interesting antibacterial activity against both gram-positive and gram-negative organisms. In this paper, we describe studies leading to identification of antibacterial agents incorporating novel pyridazine ring surrogate. In a gratifying result, the initial pyridazine-3-carboxylic acid analogues prepared were found to exhibit in vitro antibacterial activity approaching that of corresponding fluoroquinolone progenitor.     

Acid-catalyzed synthesis of oxathiolone fused chalcones. Comparison of their activity toward various microorganisms and human cancer cells line

Substituted oxathiolone fused chalcones were prepared by condensation of 4-acetyl-5-methoxy-2-oxo-benz[1,3]oxathiole with benzaldehydes under acidic conditions. The compounds were tested for cytotoxic, antibacterial, antifungal and tuberculostatic activity. Three derivatives demonstrated weak activity against HeLa cells, two were slightly active against Micrococcus luteus and Staphylococcus aureus, and one was active against Mycobacterium tuberculosis H(37)Rv.     

Novel cephalosporin derivatives possessing a substituted cinnamoyl moiety at the 7 beta-position. Synthesis, structural characterization and antibacterial activity of 3-acetoxymethyl cephalosporin derivatives

Twenty 3-acetoxymethyl cephalosporin derivatives, with various cinnamoyl (3-phenyl-2-propenoyl) substituted groups at the 7beta-position, were synthesized and evaluated for antibacterial activity in vitro. Some of these cephalosporin derivatives showed good selective activity against Gram-positive bacteria. Although substitution on the aromatic ring of cinnamoyl moiety generally reduced antimicrobial activity against Staphylococcus sp. and Enterococcus sp., a hydroxy group at the para position, and particularly ortho, para di-chloro substitution, improved the activity against methicillin resistant strains of Staphylococcus aureus (MRSA). Substitution on the double bond alpha position of the cinnamoyl moiety also affected the antimicrobial activity. A cyano group attached to this position increased activity against both negative coagulase Staphylococcus and Enterococcus sp. and extended the antibacterial spectrum towards Gram-negative bacteria.     

Inhibitory effects of spice essential oils on the growth of Bacillus species

A series of essential oils of 11 Turkish plant spices [black thyme, cumin, fennel (sweet), laurel, marjoram, mint, oregano, pickling herb, sage, savory, and thyme], used in foods mainly for their flavor, aromas, and preservation, in herbal tea, in alternative medicines, and in natural therapies, were screened for antibacterial effects at 1:50, 1:100, 1:250, and 1:500 dilutions by the paper disc diffusion method against six Bacillus species (Bacillus amyloliquefaciens ATCC 3842, Bacillus brevis FMC 3, Bacillus cereus FMC 19, Bacillus megaterium DSM 32, Bacillus subtilis IMG 22, and B. subtilis var. niger ATCC 10). All of the tested essential oils (except for cumin) showed antibacterial activity against one or more of the Bacillus species used in this study. Generally, the essential oils at 1:50 and 1:100 levels were more effective. Only one essential oil (laurel) was not found effective against the tested bacteria. The bacterium most sensitive to all of the spice essential oils was B. amyloliquefaciens ATCC 3842. Based on the results of this study, it is likely that essential oils of some spices may be used as antimicrobial agents to prevent the spoilage of food products.     

Structure-antibacterial activity of arylcarbonyl- and arylsulfonyl-piperazine 5-triazolylmethyl oxazolidinones

A series of novel arylcarbonyl- and arylsulfonyl-piperazinyl 5-triazolylmethyl oxazolidinones were synthesized and tested against a panel of Gram-positive and Gram-negative bacterial clinical isolates. The arylcarbonyl oxazolidinone derivatives showed strong in vitro antibacterial activity against susceptible and resistant Gram-positive pathogenic bacteria and were more active than the arylsufonyl derivatives. Substitution of varied electron-withdrawing and electron-donating groups on the phenyl ring in the arylcarbonyl series did not alter antibacterial activity significantly. However, in the arylsufonyl series, methyl substitution on the phenyl ring resulted in the loss of antibacterial activity. Antibacterial activity could not be directly correlated with the calculated partition coefficient (ClogP) values in this series of compounds.     

Examination of growth inhibitory properties of synthetic chalcones for which antibacterial activity was predicted

A large series of chalcones were synthesized and studied against Staphylococcus aureus and Escherichia coli. Chalcones were either unsubstituted in ring A or possessed 4'-chloro or 3',4',5'-trimethoxy groups. Their other ring B was variously substituted. It was found that the anti-staphylococcal activity of chalcones was related to the energy difference between the two highest occupied molecular orbitals (HOMO and HOMO-1). Presence of hydroxyl group in ring B was not a determinant factor for the anti-staphylococcal activity, but the lipophilicity of ring A of the hydroxyl chalcones was of importance.     

QSAR studies on benzoylaminobenzoic acid derivatives as inhibitors of beta-ketoacyl-acyl carrier protein synthase III

Fatty acid biosynthesis is essential for most of the bacterial survival. Components of this biosynthetic pathway have been identified as attractive targets for the development of new antibacterial agents. FabH, beta-ketoacyl-ACP synthase III, is a attractive target since it is central to the initiation of fatty acid biosynthesis. Quantitative structure-activity relationship (QSAR) studies have been carried out on a series of benzoylaminobenzoic acid derivatives as potent inhibitors of FabH and antibacterial activity against Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecalis, Neisseria meningitidis and Escherichia coli, which demonstrate FabH inhibitory activity in cell free and whole cell system. The QSAR studies revealed that inhibitory activity increases with increase in hydrophobicity, molar refractivity, aromaticity, and presence of OH group (on x position of the nucleus). On the other side presence of hetero-atoms like N, O, or S at R(1) position of the nucleus decreases the inhibitory activity. The comparison of QSAR between the FabH inhibitory activity and antibacterial activity against S. aureus, S. pneumoniae, S. pyogenes, E. faecalis, N. meningitidis also demonstrates that the hydrophobicity, aromaticity and presence of OH group (on x position of the nucleus) are conducive for the inhibitory activity.     

Functionalized chalcones with basic functionalities have antibacterial activity against drug sensitive Staphylococcus aureus

A library of chalcones with basic functionalities were evaluated for antibacterial activity against drug sensitive strains of Staphylococcus aureus and Escherichia coli. The most active compounds were 2-52 and 2-57 (MIC 6.3muM S. aureus). These compounds had no activity against E. coli (MIC>100muM). Both compounds were characterized by a ring A that was substituted with 2-hydroxy-4,6-dimethoxy-3-(1-methylpiperidin-4-yl) groups. The phenolic OH and 1-methylpiperidinyl groups were required for activity but the phenolic OH may play a more critical role. While the compounds were comparable to licochalcone A in terms of antibacterial activity, they caused less hemolysis of sheep erythrocytes at high concentrations (100muM). It was noted that the structural requirements for limiting hemolytic activity were less stringent than those required for antibacterial activity. The present findings suggest that the chalcone framework is an attractive template for optimization to achieve better potency, lower toxicity and a wider spectrum of antibacterial activity.     

家蝇抗菌物质诱导及高温处理后的抑菌活性

目的探讨家蝇幼虫经针刺诱导产生的抗菌物质经不同温度处理不同时间后的抑菌活性。方法室内饲养的家蝇3龄幼虫,经针刺诱导48h后提取血淋巴,100℃处理10s和30s及1、3、5min,80℃和60℃处理30s、1、3、5、10min后,采用磷酸盐缓冲液制备离心上清样品,分别观察记录其对溶壁微球菌和金黄色葡萄球菌的抑菌效果。结果经100、80℃处理后,对溶壁微球菌的抑菌环随处理时间的延长而环直径减小,60℃处理不同时间对溶壁微球菌的抑菌环大小无明显影响。100℃处理1min后以及80℃处理3min后对金黄色葡萄球菌无明显的抑菌环产生,60℃处理不同时间对金黄色葡萄球菌的抑菌环直径无明显影响。结论家蝇幼虫经针刺诱导产生的抗菌物质,其抑菌活性对高温有一定的稳定性,80～100℃加热处理,抑菌活性随处理时间延长而减弱,60℃高温处理10s至10min对其抑菌活性无明显影响。     

Synthesis, stereochemistry and antimicrobial evaluation of some N-morpholinoacetyl-2,6-diarylpiperidin-4-ones

In a search for new leads towards potent antimicrobial agents, an array of novel N-morpholinoacetyl-2,6-diarylpiperidin-4-ones has been synthesized and their in vitro antibacterial activity against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Salmonella typhi and antifungal activity against Candida albicans, Rhizopus sp., Aspergillus niger and Aspergillus flavus were evaluated. Structure and stereochemistry of all the N-morpholinoacetyl-2,6-diarylpiperidin-4-ones have been analyzed using (1)H and (13)C NMR spectroscopic techniques. In all the cases, amide N-CO group is preferentially in coplanar orientation with respect to the dynamically averaged plane of the piperidone ring. Further, all the symmetrically substituted compounds 19, 23, 24, 26 and 27 are expected to adopt half boat conformations while other compounds 20-22 and 25 adopt twist-boat conformations. Structure-activity relationship results for these nine compounds have shown that compounds 26 and 27 exerted excellent antibacterial activity against all the bacterial strains used except 27 against S. aureus. Against C. albicans and A. flavus, compound 24 recorded excellent antifungal activities while against Rhizopus sp., compound 25 showed potent activities. The obtained results may be used as key step for the building of novel chemical compounds with interesting antimicrobial profiles comparable to that of the standard drugs.     

Antiproliferative effect of Baylis-Hillman adducts and a new phthalide derivative on human tumor cell lines

In this work we report our results concerning the study on the in vitro antiproliferative activity of 18 Baylis-Hillman adducts and some derivatives against a panel of humor tumor cell lines. A brief qualitative structure-activity relationship study indicated that carbon-carbon double bond and the presence of an electron-withdrawing substituent at the aromatic ring are essential for the activity. A quinoline-phthalide derivative has exhibited a potent effect on the proliferation of all cell lines. It is interesting to note their special cytotoxic activity against NCIADR cell line.     

Antibacterial Activity and Epigenetic Remodeling of Essential Oils from Calabrian Aromatic Plants

Natural compounds have historically had a wide application in nutrition. Recently, a fundamental role has been identified for essential oils extracted from aromatic plants for their nutritional, antimicrobial, and antioxidant properties, and as food preservatives. In the present study, essential oils (EOs) from ten aromatic plants grown in Calabria (Italy), used routinely to impart aroma and taste to food, were evaluated for their antibacterial activity. This activity was investigated against Escherichia coli strain JM109, and its derived antibiotic-resistant cells selected by growing the strain at low concentrations of ampicillin, ciprofloxacin, and gentamicin by measuring the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC). Although all the essential oils showed bactericidal activity, those from Clinopodium nepeta, Origanum vulgare, and Foeniculum vulgare displayed the greatest inhibitory effects on the bacterial growth of all cell lines. It is plausible that the antibacterial activity is mediated by epigenetic modifications since the tested essential oils induce methylation both at adenine and cytosine residues in the genomes of most cell lines. This study contributes to a further characterization of the properties of essential oils by shedding new light on the molecular mechanisms that mediate these properties.     

Synthesis and in vitro activity of a series 1beta-methylcarbapenem derivatives

The synthesis of a new series of 1beta-methylcarbapenems having pyrrolidine and piperidine moieties is described. Their in vitro antibacterial activities against both Gram-positive and Gram-negative bacteria were tested and the effect of substituent on the pyrrolidine ring was investigated. A particular compound (IIIb) having hydroxypyrrolidine moiety showed the most potent antibacterial activity.     

Synthesis and biological evaluation of 1beta-methylcarbapenems having cyclic thiourea moieties and their related compounds

The synthesis of a new series of 1beta-methylcarbapenems having cyclic thiourea moieties is described. Their in vitro antibacterial activities against both Gram-positive and Gram-negative bacteria were tested and the effect of substituent on the pyrrolidine ring was investigated. A particular compound (IIId) having piperazine thiourea moiety showed the most potent antibacterial activity.     

The in vivo release characteristics of a multi-compartment vaginal ring releasing 3-keto-desogestrel

The results of a stage I study of a new vaginal ring releasing 3-keto-Desogestrel [3kDOG] is reported. The study design consisted of one study cycle, where the ring was used continuously for 21 days and then removed. Twenty healthy volunteers were randomly allocated to each of two study groups. On day 5 of the menstrual cycle, group A used a vaginal ring releasing 30 micrograms 3kDOG per 24 hours and group B used a 15 micrograms 3kDOG per 24 hours ring. After initial absorption of the 3kDOG a plateau phase was reached in 46 hours [group A] and 49 hours [group B]. On reaching the plateau phase, the overall decline in plasma levels during the 21 days of use was 5.24% for group A and 5.27% for group B. This represents a daily decline in plasma levels of 0.27% and 0.28% for the 30 micrograms and 15 micrograms per 24 hours rings, respectively. The plasma levels achieved by the rings were significantly different throughout (p = 0.011). On removal after 21 days, the mean removal half-life for both ring types was similar at 20.9 hours for group A and 21.1 hours for group B. It is concluded that the characteristics of the delivery system are worthy of further study as a potential means of contraception using 3kDOG delivered from a vaginal ring.     

Synthesis and antibacterial evaluation of 1beta-methyl-2-[5-(1-methoxyimino-2-substituted sulfonamide ethyl)pyrrolidin-3-ylthio]carbapenems and their related compounds

The synthesis of a new series of 1beta-methylcarbapenems having methoxyimine and substituted sulfonamide moieties is described. Their in vitro antibacterial activities against both Gram-positive and Gram-negative bacteria were tested and the effect of substituents on the pyrrolidine ring was investigated. A particular compound (IIIc) having methylaminosulfonamide moiety showed the most potent antibacterial activity.