Betul Tekiner-Gulbas

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.

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.

Oxidative stress in carcinogenesis: new synthetic compounds with dual effects upon free radicals and cancer.

DNA mutation is a very important step in carcinogenesis and elevated levels of oxidative DNA damage have been monitored in a variety of tumors. The discovery of the role of free radicals in cancer has led to a new medical approach. Minimizing oxidative damage may be a significant advance in the prevention or treatment of these diseases, since antioxidants are able to stop the free-radical formation and prevent oxidizing chain reactions. These findings have generated great interest in therapeutic antioxidant-based cancer drug development. The design and development of synthetic compounds, able to scavenge free radicals, could present a significant therapeutic advance, in particular for treating pathological conditions such as cancer. This article will outline the state of the research on the relationship between antioxidant therapy and cancer, describing the new synthetic antioxidant molecules that have anticancer activities. Investigations and association between dietary antioxidants, oxidative stress, and cancer will be also discussed.

3D-QSAR study on heterocyclic topoisomerase II inhibitors using CoMSIA

Selective topoisomerase II (Topo II) inhibitors have interested to a great extent for the design of new antitumoral compounds in recent years. Comparative molecular similarity indices analysis (CoMSIA) was performed on a series of previously synthesized benzoxazole, benzimidazole, and oxazolo(4,5-b)pyridine derivatives as eukaryotic Topo II inhibitors. A training set of 16 heterocyclic compounds was used to establish the CoMSIA model. They were constructed and geometrically optimized using SYBYL v7.0. The predictive ability of the model was assessed using a test set of 7 compounds. The best model has demonstrated a good fit having r2 value of 0.968 and cross-validated coefficient q2 value as 0.562 including steric and hydrophobic fields. The hydrophobic interactions showed a dominant role for increasing Topo II inhibitor activity and hydrophilic substituent was found more important than hydrophobic one on the 5 or 6 position of benzazole moiety. The model obtained from the present study can be useful for the modification and/or evaluation of the development of new Topo II inhibitors as potential antitumor compounds. †Presented at CMTPI 2005: Computational Methods in Toxicology and Pharmacology Integrating Internet resources (Shanghai, China, October 29–November 1 2005).

QSAR of genotoxic active benzazoles

Previously synthesized 2,5-disubstituted benzoxazole and benzimidazole derivatives, were tested for their genotoxic activity in the Bacillus subtilis rec− assay. The results revealed that 5-methyl-2-(p-aminobenzyl)benzoxazole exhibited the highest genotoxic response, which was comparable to 4-nitroquinoline 1-oxide (4-NQO), the reference agent of classical positive mutagen. Among the other tested compounds, four showed a genotoxic activity. A QSAR study revealed that structural parameters IYC2H4 and IYCH2O, indicating the bridge elements between the phenyl moiety and the fused ring system at position 2 and the quantum chemical parameter (ΔE ), showing the difference between HOMO and LUMO energies, were found significant for enhancing the genotoxic activity in these compounds. In addition, the substituent effects on positions R and R1 were found important for the activity as well as holding a substituent possessing a maximum length with a minimum width property on position R1 like alkyl groups. On the other hand, substituting position R with an electron donating group instead of electron withdrawing group increased the genotoxic activity. §Presented at the 12th International Workshop on Quantitative Structure-Activity Relationships in Environmental Toxicology (QSAR2006), 8–12 May 2006, Lyon, France.

Electrochemical Behaviors and Determinations of Some 2,5-Disubstituted Benzoxazole Compounds at the Hanging Mercury Drop Electrode

The electrochemical behaviors of N-(2-benzylbenzoxazol-5-yl)benzamide (B1), N-(2-benzylbenzoxazol-5-yl)4-nitrobenzamide (B2) and N-(2-(4-chlorobenzyl)benzoxazol-5-yl)-4-nitrobenzamide (B3) were investigated by cyclic voltammetry (CV), square wave voltammetry (SWV), differential puls voltammetry (DPV), chronoamperometry (CA) and bulk electrolysis (BE) techniques in dimethylsulfoxide (DMSO) containing 0.1 M tetrabutylammonium tetrafluoroborate (TBATFB). The number of electrons transferred and diffusion coefficients were calculated by using chronoamperometry and bulk electrolysis techniques. Standard heterogeneous rate constants for the electrochemical reduction were calculated by Klingler-Kochi technique. The data obtained showed that the quantitative determination of benzoxazoles could be done by using DPV and SWV rapidly and sensitively. For the DPV technique, linear working ranges for B2 and B3 were found to be (6.0 10-4.0 10) M and (1.0 10-2.0 10) M respectively. The corresponding ranges for these compounds found by SWV were (6.0 10-4.0 10) M and (1.0 10-2.0 10) M. The detection limits for B2 obtained from DPV and SWV were calculated to be 1.33 10 M and 1.76 10 M respectively. The detection limits with B3 deplicted to be almost the same.