Semisynthesis and antimicrobial activity of novel guttiferone-A derivatives

Six derivatives of guttiferone-A (LFQM-79, 80, 81, 82, 113 and 114) were synthesized and evaluated for their antimicrobial activity against the opportunistic or pathogenic fungi Candida albicans (ATCC 09548), Candida glabrata (ATCC 90030), Candida krusei (ATCC 6258), Candida parapsilosis (ATCC 69548), Candida tropicalis (ATCC 750), Cryptococcus neoformans (ATCC 90012), Trichophyton tonsurans, Microsporum gypseum and also against the opportunistic and pathogenic Gram-positive bacteria Staphylococcus aureus (ATCC 6538), Staphylococcus epidermidis (ATCC 12228), Bacillus cereus (ATCC 11778) and Gram-negative Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 9027), Salmonella typhimurium (ATCC 14028), Proteus mirabilis (ATCC 25933). The antimicrobial activities of derivatives were compared with guttiferone-A and they presented to be more potent than the original molecule and sometimes greater than standard drugs established in therapeutics. The current study showed that derivatives of guttiferone-A possess potent antimicrobial activity and are relatively non-cytotoxic, which reveal these new molecules as promising new drug prototype candidates, with innovative structural pattern.     

Synthesis and antimicrobial activity of polyhalo isophthalonitrile derivatives

A series of polyhalo isophthalonitrile derivatives (3 and 4) that incorporate a variety of substituents at the 2-, 4-, 5- and/or 6-positions of the isophthalonitrile moieties have been designed and synthesized. These derivatives were evaluated for their antimicrobial activity against Staphylococcus aureus, Bacillus cereus (Gram-positive bacteria), Escherichia coli, Pseudomonas aeruginosa (Gram-negative bacteria); and Candida albicans (Fungi). Compounds 3 and 4 showed stronger inhibition of Gram-positive bacteria and fungi growth, and the antimicrobial ability of compound 3j (a 4-(benzylamino)-5-chloro-2,6-difluoro analog, MIC[SA] = 0.5 μg/mL; MIC[BC] = 0.4 μg/mL; MIC[CA] = 0.5 μg/mL) were close to nofloxacin and fluconazole and identified as the most potent antimicrobial agents in the series. The preliminary analysis of structure–activity relationships is also discussed.     

Antifungal activity of soybean and chickpea isoflavones and their reduced derivatives

The fungicidal activity of the isoflavones from soybean (Glycine max) and chickpea (Cicer arietinum) has been studied on three food and forage contaminating fungi, Aspergillus ochraceus, Penicillium digitatum and Fusarium culmorum. The reduced derivatives of the corresponding isoflavones—the isoflavanones and the isoflavans—were also included in the investigation. For the first time in a comparative study it is shown that isoflavones and isoflavanones are variable in their activity whereas the isoflavans are moderately active inhibitors of fungal growth.     

Synthesis and antimicrobial activity of new adamantane derivatives I

A series of fourteen derivatives of adamantane was synthesised. The new compound 4-(adamant-1-ylmethoxycarbonyl)phthalanhydride obtained from 1-adamantane-methanol and trimellitic anhydride chloride appeared very useful for preparation of a number of N-substituted phthalimides. Antimicrobial activity of the newly obtained derivatives such as, for example, 4-(adamant-1-ylmethoxycarbonyl)-N-(5-carboxypentamethylene)p hthalimide or 4-(adamant-1-ylmethoxycarbonyl)-N-(L-alanyl)phthalimide was tested against Staphylococcus aureus, Bacillus sp., Micrococcus flavus and Enterococcus faecium. The minimal inhibitory concentration (MIC) for these compounds against S. aureus were 0.022 and 0.05 microg/ml, respectively.     

New chitosan derivatives with potential antimicrobial activity

A series of four water-soluble chitosan derivatives differing in molecular mass, hydrophobicity, and charge was synthesized and tested for the intensity of their effects on Gram-negative and Gram-positive bacteria. It was shown that the tested compounds allowed the penetration of ethidium bromide into the bacteria, which showed increased permeability of their cell walls under the effect of chitosans. The tolerance to various chitosan derivatives differed in Gram-negative and Gram-positive bacteria. The Gram-negative bacteria were the most responsive to high-molecular chitosan and the Gram-positive ones, to N-,O-carboxypropylchitosan, whereas high-molecular chitosan had little effect. Research on the correlation between the structure and activity of the studied compounds revealed that depolymerization of chitosan reduced, and introduction of hydrophobic substantives in chitosan molecule significantly enhanced its permeability effect on bacterial cell walls. The obtained results provide a basis for the construction of new chitosan derivatives with antimicrobial activities.     

Antifungal activity of some 3-phenoxy-l,2-epoxypropane derivatives

To protect polymers from microbial attack it is most advantageous to use compounds chemically related to the polymers. In the course of solving the problem of protection of epoxide polymers it was found that, in addition to their insecticidal activity, some of the chlorinated derivatives of 3-phenoxy-1, 2-epoxypropane possessed a pronounced fungistatic activity. The most efficient of these compounds was 3-(2,6-dichlorophenoxy)-l,2-epoxypropane, followed by 3-(2-chlorophenoxy)-l,2-epoxypropane, 3-phe-noxy-l,2-epoxypropane and 3-(2,4,6-triehlorophenoxy)-l,2-epoxypropane, all of which completely blocked the growth of a test fungus at concentrations below 0.05%. 3-(4-chlorophenoxy)-l,2-epoxypropane inhibited at a concentration of 0.1%, 3-pentachlorophenoxy-l,2-epoxypropane at a concentration of 2%.     

Novel gratisin derivatives with high antimicrobial activity and low hemolytic activity

The substitution of each constituent amino acid residue of gratisin (GR) with Ala residue indicated that each side chain structure of the constituent amino acid residues affect largely the antibiotic and hemolytic activities of GR. Among them, the substitution of Pro residues at positions 5 and 5′ with a cationic amino acid residues (Lys and Arg) results the high antibiotic activity and the low toxicity against human blood cells. Thus, we have found a novel position on the scaffold of GR at Pro^5,5′ residues whose modification will significantly lower the unwanted hemolytic activity and enhance the desired antibiotic activity.     

Regulation of T-cell-derived protein kinase C activity by vitamin A derivatives

Protein kinase C (PKC) is a ubiquitous enzyme linked to transmembrane signal transduction. It regulates agonist-mediated activation of intracellular events that result in growth and differentiation in a variety of cells and tissues. PKC is the cellular receptor for phorbol ester tumor promoters, such as 12-O-tetradecanoylphorbol-13-acetate (TPA), that bind to, and directly activate, this enzyme. Vitamin A analogs (retinoids) have been known to antagonize biologic effects of phorbol esters, e.g., promotion of skin tumor formation; however, the extract mechanism(s) of this action is not clear. To analyze the effects of retinoids on T-cell-derived PKC, we partially purified the enzyme from human leukemic T cells (Jurkat) and examined the effects of different vitamin A analogs on its activity. Furthermore, the regulatory effects of retinoids on PKC activity were compared with those of common membrane phospholipids. Retinal inhibited PKC activation induced by TPA, as well as by diacylglycerol, the physiologic activator of PKC. The observed inhibition resulted from competition with phospholipid (phosphatidylserine) and was selective for the phospholipid-dependent C kinase; cAMP-dependent protein kinase, which is phospholipid-independent, was not affected by retinal. The inhibitory effect of retinal on PKC activity was similar to that of phosphatidylcholine. Retinoic acid, in contrast to retinal, induced a Ca2+-dependent activation of PKC, thus substituting for phosphatidylserine. Furthermore, PKC activation by retinoic acid was similar to that by phosphatidylserine, the natural phospholipid cofactor, in that both could be inhibited by phosphatidylcholine and augmented by phosphatidylinositol. The inhibition or activation of PKC by retinal or retinoic acid, respectively, was independent of whether the terminal aldehyde (retinal) or carboxyl (retinoic acid) groups were in the trans or cis configuration. Other vitamin A analogs tested did not affect PKC activity. The results demonstrate that different retinoids and phospholipids may have positive or negative cooperativity in PKC activation, thereby regulating its enzymatic activity and affecting the resulting intracellular activation events. These findings suggest that at least part of the biologic effects of retinoids in general, and their modulation of T-cell function in particular, may be mediated via the influence of their intracellular metabolites on PKC, and that this mechanism may account for some of the antagonistic effects of retinoids on TPA-mediated responses in cells.     

Reactivity of vitamin A derivatives and analogues with vitamin A antibodies

Vitamin A antibodies were obtained using retinoic acid conjugated to human serum albumin as an immunogen. The following constraints governed the reactivity of vitamin A analogues with such an anti-serum. The stereochemistry of the side chain is relatively unimportant, and 9- and 13-cis retinal react almost as well as all-trans retinal. The nature of the ring is important; all of the compounds that react readily carry a beta-ionic ring; all of the compounds bearing an aromatic ring react poorly; the two compounds that display intermediate reactivity have non-aromatic 6- and 5-membered rings, respectively.     

Synthesis and antimicrobial activity of amide derivatives of polyether antibiotic-salinomycin

For the first time a direct and practical approach to the synthesis of eight amide derivatives of polyether antibiotic-salinomycin is described. The structure of allyl amide (3a) has been determined using X-ray diffraction. Salinomycin and its amide derivatives have been screened for their in vitro antimicrobial activity against the typical gram-positive cocci, gram-negative rods and yeast-like organisms, as well as against a series of clinical isolates of methicillin-resistant Staphylococcus aureus and methicillin-sensitive S. aureus. Amides of salinomycin have been found to show a wide range of activities, from inactive at 256 μg/mL to active with MIC of 2 μg/mL, comparable with salinomycin. As a result, phenyl amide (3b) was found to be the most active salinomycin derivative against gram-positive bacteria, MRSA and MSSA.     

Synthesis, antimicrobial activity and cytotoxicity of novel oxadiazole derivatives

In the present study, 5-substituted-1,3,4-oxadiazolin-2-thiones (1a-b) were synthesized via the ring closure reactions of appropriate acid hydrazides with carbon disulphide. N-(Benzothiazol-2-yl)-2-[[5-substituted-1,3,4-oxadiazol-2-yl]sulfanyl]acetamide derivatives (3a-j) were obtained by the nucleophilic substitution reactions of 5-substituted-1,3,4-oxadiazolin-2-thiones (1a-b) with N-(benzothiazol-2-yl)-2-chloroacetamides. The chemical structures of the compounds were elucidated by IR, (1)H NMR, (13)C NMR and FAB(+)-MS spectral data and elemental analyses. The synthesized compounds were screened for their antimicrobial activities against Micrococcus luteus, Bacillus subtilis, Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, Listeria monocytogenes and Candida albicans. All compounds except compound 3h exhibited the highest antibacterial activity against P. aeruginosa. Among all compounds (3a-j), the compounds bearing 4-methoxyphenoxymethyl moiety on oxadiazole ring (3a-e) exhibited the highest inhibitory activity against C. albicans. Although compound 3j did not possess 4-methoxyphenoxymethyl moiety on oxadiazole ring, this derivative also exhibited the same level of anti-candidal activity. The compounds were also investigated for their cytotoxic effects using MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Compound 3a exhibited the highest cytotoxic activity, whereas compound 3g possessed the lowest cytotoxic activity against NIH/3T3 cells.     

Synthesis and antimicrobial activity of some isoindolin-1-ones derivatives

A range of N-substituted isoindolin-1-ones was prepared and their potential as novel antimicrobial agents was investigated. MIC values for active compounds were determined and reported.     

Synthesis and antimicrobial activity of (E) stilbene derivatives

Plants use multiple defence mechanisms comprising both constitutive and inducible barriers to prevent entering of phytopathogenic micro-organisms. In many plant species one of the most efficient responses to combat attacking microbes is the rapid synthesis of antimicrobial low molecular weight phytoalexins, for example, resveratrol, 3,5,4'-trihydroxystilbene (1). Resveratrol and its natural derivatives, however, display only moderate antimicrobial effects. Nevertheless, resveratrol may be a useful lead structure for the chemical synthesis of antimicrobials. In this study, several series of stilbenes have been synthesized, starting from the aldehydes using Wittig reactions to access the corresponding styrenes that were subjected to Mizoroki-Heck reactions to yield the stilbenes in good yields. The stilbenes were tested in an agar diffusion assay against several bacteria and fungi. For some of these compounds the inhibiting zones for bacteria and fungi were comparable with those of the antibiotics tetracycline, streptomycin, ampicillin, or kanamycin, directed against prokaryotes, and nourseothricin or hygromycin controlling fungi, respectively.     

Synthesis and antimicrobial activity of some new hydrazone-bridged thiazole-pyrrole derivatives

In this work, we synthesized fourteen different compounds which contain hydrazone bridged thiazole and pyrrole rings. For this purpose, pyrrole-2-carboxaldehydes were reacted directly with thiosemicarbazide in ethanol and then obtained thiosemicarbazones were condensed with α-bromoacetophenone derivatives (Hantzsch reaction) to give 1-substituted pyrrole-2-carboxaldehyde [4-(4-substituted phenyl)-1,3-thiazol-2-yl] hydrazones. The structures of the obtained compounds were elucidated by using IR, ¹H-NMR and FAB⁺-MS spectral data and elemental analyses results. All of the compounds were screened for their antibacterial and antifungal activities against twelve different microorganisms by using microbroth dilution method. Ketoconazole and chloramphenicol were used as standard drugs. All of the compounds showed good activity against Staphylococcus aureus and Enterococcus faecalis.     

Antifungal properties of a plant extract I. Source and spectrum of antimicrobial activity

Batamote (Baccharis glutinosa Pers.), a plant native to the south-western desert of the United States has been recommended in local folklore for the therapy of athlete's foot (tinea pedis). An aqueous extract of the dried powdered leaves of this plant has been shown to inhibit dermatophytesin vitro. Further purification studies are in progress.     

Synthesis of new N-phenylpyrazole derivatives with potent antimicrobial activity

The versatile synthons 4-(2-bromoacetyl)-5-methyl-1-phenyl-3-phenylcarbamoyl-1H-pyrazole (3) and 4-[(E)-3-(dimethylamino)acryloyl]-5-methyl-1-phenyl-3-phenylcarbamoyl-1H-pyrazole (2) were used as precursors for the synthesis of a series of phenylpyrazoles with different aromatic ring systems at position 4. The antimicrobiological evaluation of the newly synthesized compounds was carried out in vitro assays for antifungal and antibacterial activities. Amongst the tested compounds, 4-acetyl-5-methyl-1-phenyl-3-phenylcarbamoyl-1H-pyrazole (1), 4-[(E)-3-(dimethylamino)acryloyl]-5-methyl-1-phenyl-3-phenylcarbamoyl-1H-pyrazole (2), 4-(2-bromoacetyl)-5-methyl-1-phenyl-3-phenylcarbamoyl-1H-pyrazole (3) and 4-(2-aminothiazol-4-yl)-5-methyl-1-phenyl-3-phenylcarbamoyl-1H-pyrazole (17) showed interesting antimicrobial properties. In particular, all tested compounds produced inhibitory effects against pathogenic yeast (Candida albicans) similar or superior to those of reference drug. In addition, compound 3 showed excellent activity against pathogenic mould (Aspergillus). From structure-activity relationship (SAR) point of view, the attachment of bromoacetyl moiety to pyrazole ring can be considered as a breakthrough in developing a new therapeutic antifungal agent related to phenylpyrazole system.     

The antimicrobial activity of lapachol and its thiosemicarbazone and semicarbazone derivatives

Lapachol was chemically modified to obtain its thiosemicarbazone and semicarbazone derivatives. These compounds were tested for antimicrobial activity against several bacteria and fungi by the broth microdilution method. The thiosemicarbazone and semicarbazone derivatives of lapachol exhibited antimicrobial activity against the bacteria Enterococcus faecalis and Staphylococcus aureus with minimal inhibitory concentrations (MICs) of 0.05 and 0.10 µmol/mL, respectively. The thiosemicarbazone and semicarbazone derivatives were also active against the pathogenic yeast Cryptococcus gattii (MICs of 0.10 and 0.20 µmol/mL, respectively). In addition, the lapachol thiosemicarbazone derivative was active against 11 clinical isolates of Paracoccidioides brasiliensis, with MICs ranging from 0.01-0.10 µmol/mL. The lapachol-derived thiosemicarbazone was not cytotoxic to normal cells at the concentrations that were active against fungi and bacteria. We synthesised, for the first time, thiosemicarbazone and semicarbazone derivatives of lapachol. The MICs for the lapachol-derived thiosemicarbazone against S. aureus, E. faecalis, C. gattii and several isolates of P. brasiliensis indicated that this compound has the potential to be developed into novel drugs to treat infections caused these microbes.     

Preparation and antimicrobial activity of some carboxymethyl chitosan acyl thiourea derivatives

Acetyl, chloroacetyl and benzoyl thiourea derivatives of carboxymethyl chitosan (ATUCMCS, CATUCMCS, and BZTUCMCS) with comparable grafting degree were synthesized and their structures were characterized by FTIR spectroscopy and elemental analyses. The antimicrobial behaviors of CMCS and its derivatives against three types of bacteria [Bacillis subtilis (B. subtilis), Staphylococous aureus (S. aureus) and Escherichia coli (E. coli)] and three crop-threatening pathogenic fungi [Aspergillus fumigate (A. fumigate), Geotrichum candidum (G. candidum) and Candida albicans (C. albicans)] were investigated. The results indicated that the antibacterial and the antifungal activities of the acyl thiourea derivatives are much higher than that of the parent CMCS. The acyl thiourea derivatives were more potent in case of Gram-positive bacteria than Gram-negative bacteria. This is illustrated for example by the values of minimum inhibitory concentration (MIC) of the ATUCMCS, CATUCMCS and BZTUCMCS against B. subtilis were 3.9, 15.6 and 62.5, respectively, while the MIC values of these derivatives against E. coli were 62.5, 125 and 500. Moreover, the antifungal activity of the CATUCMCS is higher than that of the acetyl and benzoyl thiourea derivatives. This may be due to the presence of chlorine atom.     

Synthesis,antimicrobial activity and cytotoxicity of some new carbazole derivatives

In this work, some N-(9-Ethyl-9H-carbazole-3-yl)-2-(phenoxy)acetamide derivatives were synthesised and evaluated for their antimicrobial activity and cytotoxicity. The structural elucidation of the compounds was performed by IR, ¹H-NMR, ¹³C-NMR and FAB⁺-MS spectral data and elemental analyses. The title compounds were obtained by reacting 2-chloro-N-(9-ethyl-9H-carbazole-3-yl)acetamide with some substituted phenols. The synthesised compounds were investigated for their antibacterial and antifungal activities against Micrococcus luteus, Bacillus subtilis, Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, Listeria monocytogenes and Candida albicans. The compounds N-(9-Ethyl-9H-carbazole-3-yl)-2-(4-ethylphenoxy)acetamide (2c) and N-(9-Ethyl-9H-carbazole-3-yl)-2-(quinolin-8-yloxy)acetamide (2n) showed notable antimicrobial activity. The compounds were also studied for their cytotoxic effects using MTT assay, and it was seen that 2n had the lowest cytotoxic activity against NIH/3T3 cells.