New heterocyclic derivatives of benzimidazole with germicidal activity. II. Mechanism of action of fluoro-5-(nitro-2'-furyl)-2-benzimidazole in B. subtilis and C. albicans

Study of the microbiological activity of 5-fluoro-(2'-nitrofuryl)-2-benzimidazole F-O-NO2 (I) was continued. The substance was tested on cultures of B. subtilis and C. albicans. From the microbial strains studied, the mortality rate, the minimum inhibitory and bacterial concentrations and the cytotoxicity were determined. The action mechanism was studied using tritiated leucin, uracil and thymidine. Acute toxicity in the mouse (DL50 = 275 mg/kg) was also determined. The germicidal activity of (II), homologous N-ethyl derivative of (I), was also studied. On the basis of the results obtained, a possible mechanism of action of compound (I) is discussed.     

New heterocyclic derivatives of benzimidazole with germicidal activity--IX--HPLC detection of 5-fluoro-2-(5'-nitro-2'-furyl)benzimidazole (F-O-NO2) in biological samples

The HPLC technique for the isolation and quantitation of 5-fluoro-2-(5'-nitro-2'-furyl)benzimidazole (F-O-NO2), previously described by the same Authors, in biological samples from mice is reported. Evidence is given that the highest biological concentration and the time needed for reaching it depend both on the dose and on the administration route. In fact, almost the same maximal biological concentration of F-O-NO2 (about 0.18 micrograms/mouse) is reached after 60 min from either 40 mg/Kg IP or 200 mg/Kg os drug administration, whereas the maximal biological concentration of F-O-NO2 (5.75 micrograms/mouse) is reached after 30 min from 120 mg/Kg IP drug administration.     

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.     

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.     

Semisynthetic cephalosporins with antifungal activity: laboratory studies on 2-pyridinethiol 1-oxide cephalosporins

Cephalosporins are chemotherapeutic agents whose spectrum and use are limited to antibacterial activity. Therefore, it was of interest to find several new semisynthetic cephalosporins which possess in vitro antifungal activity against Trichophyton mentagrophytes, Candida albicans and certain other yeasts. Five new cephalosporins containing the 2-pyridinethiol 1-oxide grouping were examined. Four with this heterocyclic moiety in the 3-position were found to have activity. One with the grouping in the 7-acyl-side chain was inactive. The degree of the antifungal activity was influenced by the substituent at the 7-position. The cephalosporin with a p-hydroxyphenylglycyl side chain was the most potent against the fungal strains studied. Despite this in vitro antifungal activity, none of the compounds protected mice against a systemic Candida albicans infection. All of these cephalosporins had broad spectrum in vitro and in vivo antibacterial activity.     

Synthesis and antimicrobial activity of some 5-[2-(morpholin-4-yl)acetamido] and/or 5-[2-(4-substituted piperazin-1-yl)acetamido]-2-(p-substituted phenyl)benzoxazoles

In this study, a series of twelve novel 5-[2-(morpholin-4-yl)acetamido] and/or 5-[2-(4-substituted pip-erazine-1-yl)acetamido]-2-(p-substituted phenyl]benzoxazole derivatives have been synthesized and their structures were confirmed by IR, (1)H NMR, and mass spectral data. These compounds were prepared by reacting 5-(2-chloroacetamido)-2-(4-p-substituted-phenyl)benzoxazoles, which were obtained by using 5-amino-2-[p-substituted-phenyl]benzoxazoles with chloroacetyl chloride, in the presence of morpholine or 1-substituted piperazines. All synthesized compounds 3-14 were tested by using the method of twofold serial dilution technique for in vitro activities against certain strains of Gram-positive, Gram-negative bacteria as well as the yeasts Candida albicans, Candida krusei, and Candida glabrata in comparison with standard drugs. Microbiological results showed that the newly synthesized compounds possessed a broad spectrum of activity, showing MIC values of 3.12-50 mug/mL against the Candida species.     

2, 3-Bis(5-alkyl-2-thiono-1, 3, 5-thiadiazin-3-yl) propionic acid: one-pot domino synthesis and antimicrobial activity

In a search for promising antibacterial and antifungal compounds, two new series of 2, 3-bis(5-alkyl-2-thiono-1, 3, 5-thiadiazin-3-yl)propionic acid 1 and their corresponding N, N-dimethylpropionamide 6 have been synthesized. The reaction of 2, 3-diaminopropionate 3, carbon disulfide, formaldehyde, and the appropriate alkyl amines furnished the title compound 1. N, N-dimethylpropionamides 6 were obtained by the reaction of 1 with dimethyl amine in the presence of POCl(3). The newly prepared compounds were screened in vitro against certain strains of Gram-positive and Gram-negative bacteria and compared with nalidixic acid and ciprofloxacin. Moreover, the title compounds were tested for their antifungal activity in vitro against Candida albicans, phytopathogenic, Penicillum expansum and Trichoderma hazianum, and aflatoxin-producing Aspergillus flavus. These compounds exhibit varied activity against the tested pathogenic bacteria and remarkable inhibitory effects on growth or sporulation of some of the tested fungal species.     

Synthesis and antimicrobial activity of 3-(4'-hydroxy-3'-methylphenyl)-5-[(substuted) phenyl]-4,5-dihydro-1H-1-pyrazolyl-4-pyridylmethanone derivatives

A series of 3-(4'-hydroxy-3'-methylphenyl)-5-[(substituted) phenyl]-4,5-dihydro-1H-1-pyrazolyl-4-pyridylmethanone derivatives were synthesized by the reaction between isoniazid (INH) and various chalcones and were tested for their antimicrobial activity in vitro against Staphylococcus aureus 209p, Escherichia coli ESS 2231, Aspergillus fumigatus, Candida albicans, Candida albicans ATCC 10231, Candida krusei GO3 and Candida glabrata HO5. Among the synthesized compounds, all the compounds possess the significant antibacterial activity. Compounds I(III) and I(x), i.e. 3-(4'-hydroxy-3'-methylphenyl)-5-(4"-dimethylaminophenyl)-4,5-dihydro-1H-1-pyrazolyl-4-pyridyl methanone and 3-(4'-hydroxy-3'-methylphenyl)-5-(2",6"-dichlorophenyl)-4,5-dihydro-1H-1-pyrazolyl-4-pyridylmethanone were found to be the most active agents against used bacterial and fungal strains with minimum inhibitory concentration of less than 0.5 microg/mL and were equally active as standard drugs Ofloxacin and Fluconazole.     

In vitro and in vivo antifungal activities of the eight steroid saponins from Tribulus terrestris L. with potent activity against fluconazole-resistant fungal pathogens

Antifungal activity of natural products is being studied widely. Saponins are known to be antifungal and antibacterial. We have isolated eight steroid saponins from Tribulus terrestris L., namely TTS-8, TTS-9, TTS-10, TTS-11, TTS-12, TTS-13, TTS-14 and TTS-15. TTS-12 and TTS-15 were identified as tigogenin-3-O-beta-D-xylopyranosyl(1-->2)-[beta-D-xylopyranosyl(1-->3)]-beta-D-glucopyranosyl(1-->4)-[alpha-L-rhamnopyranosyl(1-->2)]-beta-D-galactopyranoside and tigogenin-3-O-beta-D-glucopyranosyl(1-->2)-[beta-D-xylopyranosyl(1-->3)]-beta-D-glucopyranosyl(1-->4)-beta-D-galactopyranoside, respectively. The in vitro antifungal activities of the eight saponins against six fluconazole-resistant yeasts, Candida albicans, Candida glabrata, Candida parapsilosis, Candida tropicalis, Candida krusei, and Cryptococcus neoformans were studied using microbroth dilution assay. The results showed that TTS-12 and TTS-15 were very effective against several pathogenic candidal species and C. neoformans in vitro. It is noteworthy that TTS-12 and TTS-15 were very active against fluconazole-resistant C. albicans (MIC(80)=4.4, 9.4 microg/ml), C. neoformans (MIC(80)=10.7, 18.7 microg/ml) and inherently resistant C. krusei (MIC(80)=8.8, 18.4 microg/ml). So in vivo activity of TTS-12 in a vaginal infection model with fluconazole-resistant C. albicans was studied in particular. Our studies revealed TTS-12 also showed in vivo activities against fluconazole-resistant yeasts. In conclusion, steroid saponins TTS-12 and TTS-15 from Tribulus terrestris L. have significant in vitro antifungal activity against fluconazole-resistant fungi, especially TTS-12 also showed in vivo activity against fluconazole-resistant C. albicans.     

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.     

Synthesis and microbiological activity of some N-(2-hydroxy-4-substitutedphenyl)benzamides,phenylacetamides and furamides as the possible metabolites of antimicrobial active benzoxazoles

The synthesis of some N-(2-hydroxy-4-substitutedphenyl)benzamides, phenylacetamides and furamides as the possible metabolites of benzoxazoles (II1-15) was performed in order to determine their in vitro antimicrobial activity against three Gram-positive bacteria, two Gram-negative bacteria and the fungus Candida albicans and their activities were compared with several control drugs. The compounds II11, II12, and II13 were found active at a MIC value of 12.5 microg/ml against the Gram-negative microorganism Pseudomonas aeruginosa. Most of the compounds show antibacterial activity at MIC a value of 25 microg/ml against the Gram-positive bacteria Staphylococcus aureus. For the antifungal activity against C. albicans, compound II10 was found more active than the other derivatives. The antimicrobial activity of some of these benzamides, phenylacetamides (II1 and II10) which are the possible metabolites of benzoxazoles, was also compared to their corresponding cyclic analogues III-IV. Compound II10 possesses two dilutions better antifungal activity than its cyclic analogue, benzoxazole IV, against C. albicans.     

New heterocyclic derivatives of benzimidazole with germicidal activity. III. Synthesis and activity of derivatives of (formyl-5'-furyl-2')-2-benzimidazole with different substitutions at position 5

The synthesis and germicidal properties of 28 new derivatives of furyl-2-benzimidazole are described. The compounds are substituted both in position 5 of the benzene moiety and in position 5' of the heterocycle moiety. The germicidal properties of the new molecules were tested using 9 strains of bacteria and Candida albicans. Some of them exhibited germicidal properties versus Gram + bacteria and versus Candida. Some derivatives were also tested using Mycobacterium aurum: two isonicotinoylhydrazones derivatives exhibited tubercolostatic activity comparable to that of streptomycin and not much lower than that of isoniazide.     

Novel 5-substituted 3-(2-naphthalenyl)-3-(1H-imidazol-l-ylmethy)-2-methylisoxazolidine derivatives

The synthesis and antifungal activity of a series of novel 5-substituted 3-(2-naphthalenyl)-3-(1H-imidazol-1-ylmethyl)-2- methylisoxazolidine derivatives are described. When tested in vitro in solid agar assays, some of the compounds demonstrated moderate to potent activity against Trichophyton rubrum and Candida albicans.     

Synthesis and microbiological activity of some N-(o-hydroxyphenyl)benzamides and phenylacetamides as the possible metabolites of antimicrobial active benzoxazoles: part II

The synthesis of some N-(o-hydroxyphenyl)benzamides and benzacetamides (2a-2p) in order to determine their in vitro antimicrobial activity against two Gram-positive bacteria, three Gram-negative bacteria and the fungus Candida albicans is described. The new compounds were compared with several control drugs. The derivative 2g, 4-amino-N-(o-hydroxyphenyl)benzamide, was found active at an MIC value of 25 microg/ml against the Gram-negative microorganism Klebsiella pneumoniae. Most of the compounds exhibited antibacterial activity at an MIC value of 25 microg/ml against Pseudomonas aureginosa. For the antifungal activity against C. albicans, compounds 2e, 2h and 2m were found more active than the other derivatives (MIC 12.5 microg/ml). The antimicrobial activity of some of these benzamide and phenylacetamide derivatives (2a, 2b, 2f, 2g, 2h and 2k), possible metabolites of benzoxazoles, was also compared with that of the cyclic analogues 3-8. Compound 2f possesses two dilutions better antifungal activity than its cyclic analogue the benzoxazole derivative 5 against C. albicans, while having one dilution better antibacterial activity against Streptococcus faecalis and K. pneumoniae.     

Synthesis and potent antimicrobial activity of some novel 4-(5, 6-dichloro-1H-benzimidazol-2-yl)-N-substituted benzamides

A series of 4-(5, 6-dichloro-1H-benzimidazol-2-yl)-N-substituted benzamides were synthesized and evaluated for antibacterial and antifungal activities against Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), methicillin-resistant S. epidermis (MRSE), Enterococcus faecalis, Escherichia coli and Candida albicans. Certain compounds inhibit bacterial growth with low MIC values (microg/mL). Among them, compounds 10 and 11 exhibited the greatest antibacterial activity with MIC values of 3.12 microg/mL against S. aureus, MRSA and MRSE.     

Synthesis and antimicrobial activity of some pyrrole derivatives. III--2-(4-arylpiperazino)-3-ethoxycarbonyl-5-aryl-pyrrole derivatives

The synthesis of 3-ethoxycarbonyl-5-aryl-pyrrole derivatives with an arylpiperazine group in position 2 is described. The in vitro biological investigation showed that compound (XVIII) had considerable antibacterial activity against gram-positive microorganisms and antifungal activity against Candida rugosa, while the other compounds did not show any significative activity.     

Antimycotic action of some amino-N-(5-pyrimidinyl)benzenesulfonamides

2-, 3- and 4-amino-N-(6-amino-1,4-dihydro-4-oxo-2-mercapto (or alkylthio)-5-pyrimidinyl)benzenesulfonamides were synthesized and biologically tested on different strains of Candida albicans and Candida tropicalis. Some of the 4-aminoderivatives were also tested for antibacterial properties on numerous bacterial strains. Antimycotic activity of 4-amino compounds, expressed as MIC, is around 50 micrograms/ml and higher than that of both 2-amino- and 3-aminoderivatives. In all these compounds alkyl chain length does not seem to have any notable effects on biological activity, an exception being made for some aralkyl compounds. Antibacterial activity of 4-aminoderivatives is very low for all strains tested.     

Synthesis, antibacterial and antifungal activity of some novel 3-[5-(4-substituted phenyl) 1,3,4-thiadiazole-2-yl]-2-styryl quinazoline-4(3H)-ones

A series of novel 3-[5-substituted phenyl-1,3,4-thiadiazole-2-yl]-2-styryl quinazoline-4(3H)-ones were synthesized and evaluated for antibacterial activity against pathogenic strains of Staphylococcus aureus (MTCC no. 96), Bacillus subtilis (MTCC no. 619), Pseudomonas aeruginosa (MTCC no. 424) and Escherichia coli (MTCC no. 40) and antifungal activity against Aspergillus niger, Candida albicans and Fusarium oxysporum. The cup-plate method was employed to determine the minimum inhibitory concentration (MIC) value of the compounds. Some of the compounds exhibited activity comparable to Norfloxacin. The present report reveals that synthesized 2-styryl-quinazoline-4(3H)-one exhibited better antibacterial than antifungal activity.     

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.     

Synthesis and microbiological activity of some novel N-[2-(p-substitutedphenyl)-5-benzoxazolyl]-cyclohexyl carboxamide, -cyclohexyl acetamide and -cyclohexyl propionamide derivatives

The synthesis and microbiological activity of a new series of N-[2-(p-substitutedphenyl)-5-benzoxazolyl]-cyclohexyl carboxamide, -cyclohexyl acetamide and -cyclohexyl propionamide derivatives (4-11) is 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.