Esin Aki

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 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, antimicrobial activity, pharmacophore analysis of some new 2-(substitutedphenyl/benzyl)-5-[(2-benzofuryl)carboxamido]benzoxazoles.

The synthesis and antimicrobial activity of a new series of 2-(substitutedphenyl/benzyl)-5-[(2-benzofuryl)carboxamido]benzoxazole derivatives 3-12 were described. The in vitro antimicrobial activity of the compounds was determined against some Gram-positive, Gram-negative bacteria and fungi and their drug-resistant isolates in comparison with standard drugs. Antimicrobial results indicated that the synthesized compounds possessed a broad spectrum of activity with MIC values 500-15.625 microg/ml. In the series, the most active compound against Candida krusei and Candida albicans isolate is 8 with MIC value 31.25 microg/ml. However, it is one dilution less potent than the compared fluconazole. Some of the screened compounds exhibit significant activity, having MIC value as 31.25 microg/ml in Pseudomonas aeruginosa having same activity as Rifampicin. Furthermore, considering the worth of developing new antibacterial agents against drug-resistant P. aeruginosa the present study explores the structure-activity relationship analysis of 2-(substitutedphenyl/benzyl)-5-[(2-benzofuryl)carboxamido]benzoxazoles using 3D-common features pharmacophore hypotheses approach.

Vibrational spectroscopic (FT-IR, FT-Raman, 1H NMR and UV) investigations and computational study of 5-nitro-2-(4-nitrobenzyl) benzoxazole

The optimized molecular structure, vibrational frequencies, corresponding vibrational assignments of 5-nitro-2-(4-nitrobenzyl) benzoxazole have been investigated experimentally and theoretically using Gaussian09 software package. Potential energy distribution of the normal modes of vibrations was done using GAR2PED program. The energy and oscillator strength calculated by time dependent density functional theory almost compliments with experimental findings. Gauge-including atomic orbital (1)H NMR chemical shifts calculations were carried out by using B3LYP functional with 6-31G basis set. The HOMO and LUMO analysis is used to determine the charge transfer within the molecule. The stability of the molecule arising from hyper-conjugative interaction and charge delocalization have been analyzed using NBO analysis. MEP was performed by the DFT method and the predicted infrared intensities and Raman activities have also been reported. The calculated geometrical parameters are in agreement with that of similar derivatives.

Synthesis, antimicrobial activity and QSAR studies of 2,5-disubstituted benzoxazoles

In this study, a new series of 2,5-disubstituted benzoxazoles was synthesized and their structures were elucidated by elemental analysis, MASS, 1H-NMR, 13C-NMR and IR spectral data. Newly and previously synthesized 2,5-disubstituted benzoxazole derivatives were evaluated for antibacterial and antifungal activity against standard strains and their drug-resistant isolates. Microbiological results showed that the compounds presented a large spectrum of activity having MIC values of 250–7.8 µg mL−1 against the tested microorganisms. Among the newly synthesized derivatives 3–22, compound 11 was the most active against Candida krusei out of all; however, it was one dilution less potent than standard drug fluconazole. In addition, all the new and previous compounds were more active than standard drugs ampicillin trihydrate and rifampicin against Pseudomonas aeruginosa and its gentamicin-resistant isolate. The 2D-QSAR (Quantitative Structure–Activity Relationship) analysis of a set of newly and previously synthesized benzoxazoles tested for growth inhibitory activity against methicillin-resistant Staphylococcus aureus (MRSA) was also performed by using multivariable regression analysis. The activity contributions for substituent effects of these compounds were determined from the correlation equation for predictions of the lead optimization.

QSAR and pharmacophore analysis on amides against drug-resistant S. aureus 1

Considering the worth of developing new antibacterial agents against drug-resistant Stapylococcus aureus, the present study explores the structure-activity relationships analysis of N-(2-hydroxy-4(or 5)-nitro/aminophenyl)benzamide and phenylacetamide derivatives using classical QSAR and 3D-common-feature pharmacophore hypothese approaches. QSAR analysis revealed that the compounds possessing a methylene group between the phenyl and the carboxyamido moiety played a role for decreasing the activity. On the other side, substituent effects on position R1 was found important for the activity and holding a substituent possessing a minimum width property on this position like as alkyl groups enhanced the activity. Moreover, substituting position R3 with a group enhancing the electron-donor capability of the phenolic ring system increased the potency. 3D-common-feature pharmacophore approach considered that the conformational properties of the compounds were important for the activity against drug-resistant S. aureus and compounds possessing a benzamide moiety rather than phenylacetamide structure increased the activity. Furthermore, holding NO2 and OH groups on the phenyl ring attached to the benzamide moiety was important for improving the potency against drug-resistant S. aureus. 1Presented at CMTPI 2007: Computational Methods in Toxicology and Pharmacology Integrating Internet Resources (Moscow, Russia, September 1–5, 2007).

Quantum mechanical and spectroscopic (FT-IR, FT-Raman, 1H NMR and UV) investigations of 2-(p-nitrobenzyl) benzoxazole

The optimized molecular structure, vibrational frequencies, corresponding vibrational assignments of 2(p-nitrobenzyl)benzoxazole have been investigated experimentally and theoretically using Gaussian09 software package. Potential energy distribution of the normal modes of vibrations are done using GAR2PED program. The optimized geometrical parameters are in agreement with that of similar derivatives. The energy and oscillator strength calculated by Time Dependent Density Functional Theory results almost compliments with experimental findings. Gauge-including atomic orbital H NMR chemical shifts calculations were carried out by using B3LYP functional with 6-31G basis sets. The HOMO and LUMO analysis is used to determine the charge transfer with in the molecule. The stability of the molecule arising from hyper-conjugative interaction and charge delocalization has been analyzed using NBO analysis. MEP was performed by the DFT method and the infrared and Raman intensities have also been reported. Mulliken’s net charges have been calculated and compared with the atomic natural charges. The calculated first hyperpolarizability of the title compound is 82.31 time that of the standard NLO material urea and hence is an attractive object for future studies of nonlinear optical properties. 2013 Elsevier B.V. All rights reserved.

Insight into eukaryotic topoisomerase II-inhibiting fused heterocyclic compounds in human cancer cell lines by molecular docking

Etoposide is effective as an anti-tumour drug by inhibiting eukaryotic DNA topoisomerase II via establishing a covalent complex with DNA. Unfortunately, its wide therapeutic application is often hindered by multidrug resistance (MDR), low water solubility and toxicity. In our previous study, new derivatives of benzoxazoles, benzimidazoles and related fused heterocyclic compounds, which exhibited significant eukaryotic DNA topoisomerase II inhibitory activity, were synthesized and exhibited better inhibitory activity compared with the drug etoposide itself. To expose the binding interactions between the eukaryotic topoisomerase II and the active heterocyclic compounds, docking studies were performed, using the software Discovery Studio 2.1, based on the crystal structure of the Topo IIA-bound G-segment DNA (PDB ID: 2RGR). The research was conducted on a selected set of 31 fused heterocyclic compounds with variation in structure and activity. The structural analyses indicate coordinate and hydrogen bonding interactions, van der Waals interactions and hydrophobic interactions between ligands and the protein, as Topo IIA-bound G-segment DNA are responsible for the preference of inhibition and potency. Collectively, the results demonstrate that the compounds 1a, 1c, 3b, 3c, 3e and 4a are significant anti-tumour drug candidates that should be further studied.

Genotoxic potentials and eukaryotic DNA topoisomerase I inhibitory effects of some benzoxazine derivatives

Benzoxazines are heterocyclic compounds which have been used as intermediates in the synthesis of many heterocyclic structures of biological importance as it has been reported that some of the benzoxazines were effective in promoting apoptosis and inhibiting cell proliferation. Present study contains experimental data that showed genotoxic potentials and inhibitory effects on eukaryotic DNA topoisomerase I of 16 newly synthesized benzoxazine derivatives. By rec assay, the bacterial genotoxicity assay, only four tested compounds were found genotoxic at different concentrations and four compounds showed reverse effect. RC50 values evaluated by rec assay revealed that BS5 was the most genotoxic and BS4 was the most cytotoxic compound at micromolar concentration. Compounds were also tested for their inhibitory effects on eukaryotic DNA topoisomerase I enzyme and it was found that 14 of the compounds had inhibitory effects on eukaryotic DNA topoisomerase I enzyme. The most active compounds, BS18 and BS4, showed higher inhibitory activities than the positive control drug camptothecin which is a well-known commercial topoisomerase I inhibitor.

4-Thiazolidinone Derivatives as MMP Inhibitors in Tissue Damage: Synthesis, Biological Evaluation and Docking Studies

Nine 2-(1,2-benzothiazol-3-yl)-N-(4-oxo-2-phenyl-1,3-thiazolidin-3-yl)propanamides combining a benzisothiazole and 4-thiazolidinone in one framework were designed and synthesized. The aim of the study was to verify their effectiveness to affect the inflammatory/oxidative process in which free oxygen and nitrite (ROS and RNS) radicals, inflammatory mediators, such as nuclear factor κB (NF-κB), and matrix metalloproteinases (MMPs) are involved. Docking studies of all the compounds were performed in order to explore their binding mode at the MMP-9 protein. An appreciable anti-inflammatory/potential wound healing effects of the tested compounds was highlighted. Derivative 23, bearing a 4-carboxyphenyl substituent at C2 of the 4-thiazolidinone ring, exhibited the highest activity, being able to inhibit MMP-9 at nanomolar level(IC50 = 40 nM).