Ismail Yalcin

Synthesis and antimicrobial activity of some novel 2,5- and/or 6-substituted benzoxazole and benzimidazole derivatives.

A new series of 2,5- and/or 6-substituted benzoxazoles (7a-f), benzimidazoles (8a-g) holding cyclohexyl or cyclopentyl moieties at position 2 and 5- or 6-substituted-2-cyclohexylaminomethylbenzoxazoles (9a, b) was synthesized in order to determine their antimicrobial activities and feasible structure-activity relationships. The synthesized compounds were tested in vitro against three Gram-positive, two Gram-negative bacteria and the yeast Candida albicans in comparison with several control drugs. Microbiological results showed that the synthesized compounds were possessing a broad spectrum of antibacterial activity against the tested microorganisms. 5-Chloro-2-(2-cyclohexylethyl)benzimidazole (8g) was found as the most active compound against the screened Gram-positive bacteria strains at a minimum inhibitory concentration (MIC) value of 12.5 microg/ml. However, it exhibited lower antibacterial potency than the compared control drugs. On the other side, compounds 7-9 indicated significant antibacterial activity against the Gram-negative enterobacter Pseudomonas aeruginosa having MIC values of 50 microg/ml, providing either the same effect as tetracycline or higher activity than streptomycin, but showing less potency than the compared control drug gentamycin. Moreover, the synthesized compounds also possessed antimycotic activity against the yeast C. albicans showing MIC values between 25-50 microg/ml.

The synthesis and the structure−activity relationships of some substituted benzoxazoles, oxazolo(4,5-b)pyridines, benzothiazoles and benzimidazoles as antimicrobial agents

Abstract The synthesis of a new series of 2,5-disubstituted benzoxazoles 4a–f , 2-substituted oxazolo(4,5- b )pyridines 5a, b , benzothiazoles 6a, b and benzimidazoles 7a, b is described in order to determine their antimicrobial activities and feasible structure-activity relationships (SAR). The synthesized compounds were tested in vitro against 3 Gram-positive, 3 Gram-negative, and a fungus Candida albicans , 4b, 4e and 4f were found to be more active than the others against Klebsiella pneumoniae at a MIC value of 12.5 μg/ml. All the derivatives 4–7 exhibited significant antimycotic activity against C albicans . The antibacterial and antimycotic activities of 4–7 are also compared with several standard drugs.

Synthesis and microbiological activity of some novel 5- or 6-methyl-2-(2,4-disubstituted phenyl) benzoxazole derivatives

The synthesis of a new series of 5-or 6-methyl-2-(2,4-disubstituted phenyl) benzoxazoles (4, 5) is described in order to determine their antimicrobial activities and feasible structure-activity relationships. The synthesized compounds were tested in vitro against three Gram-positive bacteria, three Gram-negative bacteria and the yeast Candida albicans, in comparison with several control drugs. Microbiological results exhibited that the synthesized compounds possess a broad spectrum of antibacterial activity against the tested microorganisms. The compounds 4b and 4c indicated some antibacterial activity against Staphylococcus aureus having a minimum inhibitory concentration (MIC) of 12.5 micrograms/ml. Moreover, the compound 5a revealed a significant antibacterial activity against the enterobacter Pseudomonas aeruginosa showing a MIC value of 25 micrograms/ml, i.e. more potent than the control drugs tetracycline and streptomycin. For the antimycotic activity against the yeast C. albicans, the derivative 4c was found to be more active than the other synthesized compounds with a MIC value of 12.5 micrograms/ml, but one-fold less potent than the control drugs oxiconazole and haloprogin.

Synthesis, biological evaluation and 2D-QSAR analysis of benzoxazoles as antimicrobial agents.

A new series of 5(or 6)-nitro/amino-2-(substituted phenyl/benzyl)benzoxazole derivatives were synthesized and evaluated for antibacterial and antifungal activities against Staphylococcus aureus, Bacillus subtilis, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Candida albicans and their drug-resistant isolate. Microbiological results indicated that the synthesized compounds possessed a broad spectrum of activity against the tested microorganisms at MIC values between > 400 and 12.5 microg/ml. The results against B. subtilis, P. aeruginosa, drug-resistant B. subtilis, drug-resistant E. coli, and C. albicans isolate for these kinds of structures are quite encouraging. The 2D-QSAR analysis of a set of newly and previously synthesized benzoxazoles tested for growth inhibitory activity against B. subtilis ATCC 6633 was performed by using the multivariable regression analysis. The activity contributions for substituent effects of these compounds were determined from the correlation equation for predictions of the lead optimization.

Some benzoxazoles and benzimidazoles as DNA topoisomerase I and II inhibitors.

Some novel fused heterocyclic compounds of 2, 5-disubstituted-benzoxazole and benzimidazole derivatives, which were previously synthesized by our group, were investigated for their inhibitory activity on both eukaryotic DNA topoisomerase I and II in a cell free system. 2-Phenoxymethylbenzimidazole (17), 5-amino-2-(p-fluorophenyl)benzoxazole (3), 5-amino-2-(p-bromophenyl)benzoxazole (5), 5-nitro-2-phenoxymethyl-benzimidazole (18), 2-(p-chlorobenzyl)benzoxazole (10) and 5-amino-2-phenylbenzoxazole (2) were found to be more potent as eukaryotic DNA topoisomerase I poisons than the reference drug camptothecin having IC50 values of 14.1, 132.3, 134.1, 248, 443.5, and 495 μM, respectively. 5-Chloro-2-(p-methylphenyl)benzoxazole (4), 2-(p-nitrobenzyl)benzoxazole (6) and 5-nitro-2-(p-nitrobenzyl)benzoxazole (8) exhibited significant activity as eukaryotic DNA topoisomerase II inhibitors, having IC50 values of 22.3, 17.4, 91.41 μM, respectively, showing higher potency than the reference drug etoposide.

Some new bi- and ter-benzimidazole derivatives as topoisomerase I inhibitors

The discovery of DNA topoisomerases has added a new dimension to the study of anticancer drugs. In the last years detailed investigation of bi- and ter-benzimidazole derivatives revealed that these compounds are a new class of topoisomerase I inhibitors that poisons mammalian topoisomerase I. In this context a survey about topoisomerase I poisoning activity and cytotoxicity of bi- and ter-benzimidazoles is given. Moreover some recent results about new derivatives, some structure-activity relationships and comparison of activity of various functional groups are discussed.

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.

High antineoplastic activity of new heterocyclic compounds in cancer cells with resistance against classical DNA topoisomerase II-targeting drugs

Twenty previously synthesized fused heterocyclic DNA‐topoisomerase II (Topo II)‐inhibiting compounds were investigated for their potential efficacy in various human cancer cell lines that were derived from different tumor entities. Moreover, different multidrug‐resistant variants of these cancer cell lines with decreased Topo II expression were investigated. In parental, drug‐sensitive cells merely the compounds BD3 and G35 showed efficacies, in terms of μM, which were similar to that of the classical Topo II inhibitor etoposide. On the other hand, most of the tested heterocyclic compounds were found more effective in drug‐resistant cells than in the parental, drug‐sensitive ones, and some of the compounds showed high antineoplastic efficacy in several drug‐resistant cell models. Compounds BD13, BD14 and BD16 exhibited high antineoplastic activities against the drug‐resistant sublines EPG85‐257RNOV and EPG85‐257RDB derived from gastric carcinoma, EPP85‐181RNOV and EPP85‐181RDB derived from pancreatic carcinoma, MCF‐7/Adr derived from breast cancer, D79/86RNOV derived from fibrosarcoma, and MeWoETO1 derived from melanoma. Furthermore, compound D23 was found highly efficient in the multidrug‐resistant variants HT‐29RNOV and HT‐29RDB derived from colon carcinoma, and compound D24 exhibited the highest antineoplastic activity among the tested compounds in the drug‐resistant subline MDA‐MB‐231ROV derived from breast cancer. In conclusion, compounds BD 13, BD 14, BD 16, D 23 and D 24 may be useful for the treatment of different multidrug‐resistant cancer cells with cross resistance against “classical” Topo II‐targeting drugs.

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.

A study on the genotoxic activities of some new benzoxazoles

The Bacillus subtilisrec assay has been specially developed to detect DNA-damaging potential in chemicals, with the rationale based on the relative difference of survival of a DNA repair combination proficient strains and its deficient strain, which is interpreted as genotoxicity. The genotoxic activities of newly (1–6) and previously (7–18) synthesized various benzoxazoles and benzimidazoles were analyzed via the B. subtilisrec assay. Newly obtained benzoxazole and benzimidazole derivatives (1–6) were synthesized in the presence of polyphosphoric acid (PPA) and 6 N HCl, respectively to detect their DNA-damaging activities. Among the tested compounds, 6-methyl-2-(o-chlorophenyl)benzoxazole (9), 5-amino-2-(p-methylbenzyl)benzoxazole (4), 5-(p-fluorobenzamido)-2-phenylbenzoxazole (13), and 2-(p-methylaminophenyl)benzoxazole (18) showed genotoxic activities having Rec50 values of 1.85, 1.74, 1.60, and 1.50 or S-probit values of 0.534, 0.482, 0.460, and 0.357, respectively. On the other hand, 2-(p-bromobenzyl)-5-methylbenzimidazole (6) and 2-benzyl-5-(p-fluorophenylacetamido)-benzoxazole (15) were exhibited a reverse effect that displayed a bacterial growth in the rec- strains while there was no any bacterial growth in rec+ strains at the same concentration.