New heterocyclic derivatives with germicidal activity. VI. Synthesis and activity of new 2-benzoxazoyl-2'-furanes and -thiophenes variously substituted in 5 and 5' positions

Seventeen derivatives of 2'-furyl-2-benzoxazole and three derivatives of 2'-thienyl-2-benzoxazole, having different substituents in the benzene moiety (position 5) and in the furanic or thiophenic ring (position 5'), are described, with the aim of studying antibacterial and antimycotic structure-activity relationships. None of the compounds show an important antibacterial and/or antimycotic activity, when tested against nine bacteria and Candida albicans cultures; in any case it was much lower than that previously reported for the corresponding benzimidazoles. It seems that the = NH group of the imidazole ring, which is absent in the benzoxazole derivatives, might be important for the biological activity of this class of compounds.     

New heterocyclic derivatives of benzimidazole with germicidal activity. V. Synthesis and activity of new derivatives of di-2-benzimidazolyl-2,5-furan

In continuation of the research in the field of germicidal and antimycotic agents, the synthesis of 14 new derivatives of di-2-benzimidazolyl-2,5-furan is described. These derivatives are differently substituted (R not equal to R') in the position 5 of the two benzene rings. These new compounds showed no germicidal or fungicidal activity, when tested on different cultures. New compounds are under investigation.     

Synthesis of new 3-substituted-5-(2-hydroxyethyl)-3,4,5,6-tetrahydro-2H-l,3,5-thiadiazine-2-thione derivatives with potential antimicrobial activity

The purpose of this study is based upon design and synthesis of a new series of flexible molecules of 3,4,5,6-tetrahydro-2H-1,3,5-thiadiazine-2-thione (THTT) derivatives depending upon incorporation of 2-aminoethanol as a part of the polar moiety in this nucleus. Thirteen derivatives of 3-substituted-5-(2-hydroxyethyl)-3,4,5,6-tetrahydro-2H-1,3,5-thiadiazine-2-thione were synthesized by reaction of the appropriate alkyl, cycloalkyl, aralkyl amine, or glycine with carbon disulphide, formaldehyde, and 2-aminoethanol. The structures of the target compounds were elucidated using spectral methods as well as elemental analyses. A mass-spectrometry study was carried out on representatives of the synthesized derivatives. The title compounds were tested for their antibacterial activity in vitro against some gram positive and gram negative bacteria. The in-vitro antifungal activity was tested against dermatophytic, saprophytic, phytopathogenic, and antagonistic fungi. In most cases, the newly synthesized compounds 4-16 exhibited a considerable inhibitory effect on the growth of some of the tested organisms in comparison to that of ampicillin or muconazole as reference drugs. Moreover, the results indicated that the polar hydroxyethyl group at the N5- and the lipophilic one at the N3-positions are essential for the antimicrobial activity of the tested compounds.     

Synthesis and microbiological activity of some novel 5-benzamido- and 5-phenylacetamido-substituted 2-phenylbenzoxazole derivatives

The synthesis and microbiological activity of a new series of 5-benzamido- and 5-phenylacetamidosubstituted-2-phenylbenzoxazole derivatives (1-26) were described. The in vitro microbiological activity of the compounds was determined against Gram-positive, Gram-negative bacteria and the yeast Candida albicans in comparison with standard drugs. Microbiological results indicated that the synthesized compounds possessed a broad spectrum of activity against the tested microorganisms. The compounds 1, 21, 25 showed higher activity than tetracycline and streptomycin against Pseudomonas aeruginosa.     

Development of new antiepileptic agents. III. Anticonvulsant activity of some derivatives of 1-(p-sulfamoylphenyl)-imidazolidinone-5 (author's transl)

A series of derivatives of 1-(p-sulfamoylphenyl)imidazolidinone-5 were tested for anticonvulsant properties against electroshock and pentylenetetrazole seizures. They were also screened for analgesic, sedative and toxic effects. The substances that had the best anticonvulsant activities were those with halogen substitution in the ortho position of the 1-phenylring of 1-(p-sulfamoylphenyl)-3-phenylimidazolidinone-5. Additional substitutions on the basic structure (imidazolidinone-5) or on the 3-phenylring diminished the anticonvulsant activity. The anticonvulsants are less toxic than diphenylhydantoin. Some of the substances exhibited feeble analgesic and sedative properties.     

Synthesis,degradation kinetics and in vitro antimicrobial activity of tetrahydro-2H-1,3,5-thiadiazine-2-thione derivatives of some beta-amino acids

Two series of tetrahydro-2H-1,3,5-thiadiazine-2-thione (THTT) derivatives were synthesized, 2a-f and 3a-f, by incorporation of beta-alanine and beta-phenylalanine, respectively, at the 5th position of the THTT moiety. Structures of these derivatives were verified by spectral and elemental methods of analyses. The lipophilic properties of the synthesized derivatives, expressed as calculated log P (Clog P), revealed that the beta-phenylalanine derivatives, 3a-f, have enhanced lipophilic characters compared to the corresponding beta-alanine analogues, 2a-f. The stability of the synthesized derivatives in aqueous buffer solution of pH 7.4, and in 80% human plasma was studied at 37 degrees C using high pressure liquid chromatography. As a general pattern, under the investigation conditions beta-phenylalanine derivatives were more labile and susceptible for chemical and enzymatic degradation than the corresponding beta-alanine analogues. Furthermore, the degradation rates of the synthesized derivatives affected by the variation of substituents on N-3 of the THTT moiety. The anti-fungal activity of the synthesized compounds was tested in vitro against different strains of fungi using the standard agar disk diffusion method. beta-Alanine derivatives, 2e and 2f, bearing an aralkyl group on the 3ed position of the THTT moiety exhibited antifungal activity against C. albicans and F. oxysporum. Furthermore, 2a, which is also a beta-alanine derivative bearing an ethyi group on the 3ed position of the THTT moiety solely showed a significant in vitro anti-bacterial activity against Bacillus serreus (Gram positive) and Serratia rhodnii (Gram negative).     

Synthesis and antibacterial activity of N-[5-chlorobenzylthio-1,3,4-thiadiazol-2-yl] piperazinyl quinolone derivatives

A series ofN-[5-(chlorobenzylthio)-1,3,4-thiadiazol-2-yl] piperazinyl quinolone derivatives (4a-1) have been synthesized by reaction of piperazinyl quinolones with 5-chloro-2-(chloroben-zylthio)-1,3,4-thiadiazoles. Their structures were confirmed by elemental analysis, IR and NMR spectra. The antibacterial activities of4a-1 against a variety of Gram-positive and Gram-negative bacteria were determined. Several compounds showed a good antibacterial activity against Gram-positive bacteria among which, compound 4e with a 2-chlorobenzylthio moiety in ciprofloxacin derivative, exhibited high activities againstStaphylococcus aureus andStaphylococcus epidermidis (MIC=0.06 μg/mL). The structure-activity relationship (SAR) study revealed that the position of chlorine atom on benzyl moiety would dramatically affect the antibacterial activities of the synthesized compounds.     

Chemotherapeutic agents with an imidazole moiety. III. Synthesis and microbiological activity of new 1,4-diarylimidazole and 1,4-pyrrolimidazolphenylene derivatives.

New 1,4-diarylimidazole and 1,4-pyrrolimidazol-phenylene derivatives were prepared in attempt to deepen S.A.R. study on chemotherapeutic agents with an imidazole moiety. Antimicrobial data in comparison with antifungal antibiotic pyrrolnitrin showed that all tested compounds are practically inactive against blastomycetes but some derivatives exhibited selective activity against strains of gram-negative bacteria. The results obtained are discussed on the basis of structure-activity relationships.     

Synthesis and antimicrobial activity of some novel 2-(p-substituted-phenyl)-5-substituted-carbonylaminobenzoxazoles

A series of 2-(p-substituted-phenyl)-5-substituted-carbonylamino benzoxazole derivatives (5-22) was synthesized and their antimicrobial activities determined in comparison to several control drugs. The synthesized compounds were tested in vitro against Staphylococcus aureus, Streptococcus faecalis and Bacillus subtilis as Gram-positive, Pseudomonas aeruginosa and Escherichia coli as Gram-negative bacteria and the yeast Candida albicans. Microbiological results showed that the compounds possessed a diffuse spectrum of antibacterial activity against these microorganisms. Compound 9 which bears a phenylacetamido moiety at position 5 and a 4-fluorophenyl group at the 2-position of benzoxazole ring was the most active derivative against S. aureus, S. faecalis and P. aeruginosa with a MIC value of 12.5 microg/ml. Compound 11 provided higher potency than the other tested compounds against B. subtilis at a MIC value of 12.5 microg/ml. Compounds 5-22 showed antifungal activity against C. albicans with MIC values between 50 and 12.5 microg/ml.     

N-substituted p-fluorobenzene sulfonamides with antimicrobial activity. I

In an extension of the investigations on fluorine derivatives of potential pharmacological interest, some new p-fluorobenzensulfonanilides were synthesized and screened in vitro against many species of Gram-positive and Gram-negative bacteria and against some strains of Candida albicans. Some of these compounds exhibited significant antibacterial activity. The relation between activity and structure revealed that the presence of chloro and trifluoromethyl groups in the aniline ring increases activity against Gram-positive bacteria. The acute toxicity in mice was also determined.     

New heterocyclic derivatives of benzimidazole with germicidal activity--VII--2-(5'-nitro-2'-furyl or 2'-thienyl) benzimidazoles with different substituents in the 5-position

In continuation of our previous research, the synthesis of 13 2-(5'-nitro-2'-furyl or 2'-thienyl) benzimidazoles with different substituents in 5 position is described. The new compounds were tested in vitro against 5 (Gram+) and 4 (Gram-) strains and a mycete Candida Albicans. All the derivatives showed a certain degree of antibacterial and antimycotic activity, which in some cases was fairly good.     

Synthesis and antimicrobial activity of some new 2-phenyl-N-substituted carboxamido-1H-benzimidazole derivatives.

Some 1H-benzimidazole-carboxamide derivatives were prepared and their antimicrobial activities against Staphyloccus aureus, Escherichia coli and Candida albicans evaluated. Compounds 18, 22, and 25 exhibited the best activity against Candida albicans.     

Antibacterial and antifungal compounds. VIII. Synthesis and antifungal activity of pyrrol derivatives similar to trichostatin A

Some p-methylbenzolpyrrole acrylic acids and related compounds were synthesized. The new pyrrole derivatives have structural features in common with trichostatin A, an antifungal antibiotic. The above acids and derivatives were tested against Candida albicans and Candida sp in comparison with miconazole, pyrrolnitrin and amphotericin B and showed very weak antifungal activities. Occasionally some activity was found against a few strains of Candida albicans and against Candida pseudotropicalis.     

Studies on pyrazine derivatives. XLVII. Synthesis and antibacterial activity of novel pyrazine derivatives with amidoxime moiety

The new pyrazine derivatives exhibiting an antibacterial activity have been synthesized. Initial amidoxime 1 was obtained in the reaction of pyrazinecarbonitrile with hydroxylamine. Upon treatment of amidoxime with methyl iodide O-methyl derivative 2 was formed. Both amidoximes were transformed into imidoyl chlorides 3, 4. Then the chloride atom in those derivatives was substituted with various secondary amines giving appropriate oximes 5-18 and O-methyl-oximes 19 and 20. The obtained compounds were tested in vitro for their tuberculostatic activity. The inhibiting concentration (MIC) values were within 25-100 microg/mL. Their activity towards 25 strains of anaerobic and 25 strains of aerobic bacteria was also studied. Three compounds exhibited activity against both types of bacteria.     

Synthesis and antimicrobial activity evaluation of some new adamantane derivatives

In this study, some new Schiff bases were synthesized as antimicrobial agents using benzaldehyde derivatives and 1- or 2-aminoadamantane. The structures of the synthesized compounds were confirmed by IR, 1H-NMR and elementary analysis. Antimicrobial activities of the synthesized compounds were tested against some bacteria and yeast-like fungi. The antimicrobial activity of the compounds was investigated by broth microdilution method using two Gram positive (Staphylococcus aureus ATCC 25923, Enterococcus faecalis ATCC 29212) and two Gram negative (Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853) bacteria and yeast-like fungi (Candida albicans ATCC 90028, Candida krusei ATCC 6258, Candida parapsilosis ATCC 22019). The antifungal activity of 1-((2-chloro-3,4-dimethoxybenzylidene) amino(adamantane (compound 3) against C. krusei and C. parapsilosis (minimal inhibitory concentration 32 micrograms/ml) was higher than that of the other tested compounds.     

Synthesis and antimicrobial activity of new 2-[p-substituted-benzyl]-5-[substituted-carbonylamino]benzoxazoles

A series of 23 new 2-[p-substituted-benzyl]-5-[p-substituted-phenyl/benzyl-carbonylamino]benzoxazole derivatives has been synthesized by reacting 5-amino-2-[p-substituted-benzyl]benzoxazoles with the appropriate carboxylic acid chlorides. The structures of the synthesized compounds were confirmed by IR and (1)H-NMR spectral data. Antimicrobial activities of the compounds were investigated using the twofold serial dilution technique against two gram-positive and two gram-negative bacteria and three Candida species in comparison with standard drugs. Microbiological results indicated that the newly synthesized 2-[p-substituted-benzyl]-5-[p-substituted-phenyl/benzyl-carbonylamino]benzoxazole derivatives (3-25) possessed a broad spectrum of activity, showing MIC values of 6.25-200 microg/mL against the gram-positive and gram-negative microorganisms tested. Moreover, they showed significant antifungal activity with MIC values of 3.12-100 microg/mL against the Candida species tested. Especially, with a MIC value of 3.12 microg/mL, 2-benzyl-5-[p-bromobenzyl-carbonylamino]benzoxazole 9 displayed the same activity against C. glabrata as the standard drug myconazol.     

Synthesis and in vitro antibacterial activity of some N-(5-aryl-1,3,4-thiadiazole-2-yl)piperazinyl quinolone derivatives

A series of N-[5-(1-methyl-5-nitro-2-imidazolyl)-1,3,4-thiadiazole-2-yl] and N-[5-(nitrophenyl)-1,3,4-thiadiazole-2-yl] piperazinyl quinolone derivatives (5a-c and 5d-l) were synthesized and evaluated for in vitro antibacterial activity against some Gram-positive and Gram-negative bacteria. The antibacterial data revealed that all nitroimidazole derivatives (5a-c) showed interesting activity against tested Gram-positive bacteria (minimum inhibitory concentration, MIC=0.008-0.03 microg/ml) while they did not show good activity against Gram-negative organisms. Despite the significant activity of nitroimidazole series, all nitrophenyl analogues (5d-l) were inactive against both Gram-positive and Gram-negative bacteria. Among all of the tested compounds, 5a (ciprofloxacin derivative in nitroimidazole series) exhibited excellent activity against Staphylococcus aureus and Staphylococcus epidermidis (MIC=0.008 microg/ml).     

Synthesis of new hexahydro- and octahydropyrido[1,2-c]pyrimidine derivatives with an arylpiperazine moiety as ligands for 5-HT(1A) and 5-HT(2A) receptors, Part 2

The synthesis of new of 4-aryl-hexahydro- (11-16) and (R,R)(S,S)4-aryl-octahydropyrido[1,2-c]pyrimidine (23-27) derivatives bearing a aryl- or heteroarylpiperazinyl moiety in position 2 is described. The derivatives of 4-aryl-hexahydro- (1-5) and (R,R)(S,S)4-aryl-octahydropyrido[1,2-c]pyrimidin-1,3-dion (17-19) served as starting compounds for further synteses. The N-alkylation of the imide moiety in compounds 1-5 and 17-19 by 1,4-dibromobutane gave the respective monbromobutyl derivatives 6-10 and 20-22. The final derivatives 11-16 and 23-27 have been produced by condensation of the obtained bromoderivatives with selected 1-aryl and 1-heteroarylpiperazines. Compounds 11-16 and 23-27 were tested for their affinity towards 5-HT(1A), 5-HT(2A) and alpha1 receptors, using a radioligand binding assay.     

New heterocyclic derivatives of benzimidazole with germicidal activity. IV--In vivo anticandida activity of 5-fluoro-2-(5'-nitro-2'-furyl) benzimidazole (F-O-NO2)

We have studied the possible in vitro and in vivo antibacterial activity of 5-fluoro-2-(5'-nitro-2'-furyl)benzimidazole (F-O-NO2). Our data demonstrate that F-O-NO2 is able to inhibit the in vitro growth of different mycetes and bacteria, including Candida albicans and Cryptococcus neoformans. We also tested the possible in vivo activity against Candida albicans. The results clearly show that treatment with F-O-NO2 is able to significantly augment the survival of all treated animals; in particular, when injected i.p. at the dose of 120 mg/kg, 30' or 1 hr after Candida albicans challenge, it givens a MST (Medium Survival Time) longer than 60 days. These data demonstrate that F-O-NO2 has antibacterial and antimycotic activity.     

Synthesis and 5-HT1A/5-HT2A receptor activity of N-(4-arylpiperazin-1-yl)alkyl derivatives of 2-azaspiro([4.4]nonane and [4.5]decane-1,3-dione

Two series of N-[(4-arylpiperazin-1-yl)-alkyl]-2-azaspiro[4.4]nonane (5-10) and [4.5]decane-1,3-dione (11-16) derivatives were synthesized and their serotonin 5-HT1A and 5-HT2A receptor affinities were determined. Compounds with the methylene spacer (5-7 and 11-13) exhibited low 5-HT1A/5-HT2A receptor affinity, in contrast to their ethylene analogues regarded as potent 5-HT1A ligands, especially those containing a cyclohexane moiety (14-16; Ki = 5.1, 2.7 and 4.3 nM, respectively) in the 3-position of the pyrrolidine-2,5-dione ring. Moreover, derivatives with 3-chloro substituent (10 and 14) showed distinct affinity for 5-HT2A receptors. The functional activity of compounds 10, 14, 15 and 16 was tested in vivo in the commonly used animal models. In those experiments, the tested compounds showed features of agonists of pre- and postsynaptic (14), agonists of presynaptic and antagonists of postsynaptic (10, 15), or agonists of postsynaptic (16) 5-HT1A receptors. Additionally, 10 and 16 exhibited properties of potential 5-HT2A receptor antagonists. The above results suggested a crucial role of the spacer between the amide fragment and 4-arylpiperazine moiety, as well as of the size of the cycloalkyl ring at the 3-position of pyrrolidine-2,5-dione ring in functional 5-HT1A/5-HT2A properties.