Synthesis and biological activity of some new benzoxazoles.

The synthesis and antimicrobial activity of a new series of 5-ethylsulphonyl-2-(substituted-phenyl/substituted-benzyl and/or phenylethyl)benzoxazole derivatives (3a-3t) except 3a, 3g, 3h, 3k [R.S. Pottorf, N.K. Chadha, M. Katkevies, V. Ozola, E. Suna, H. Ghane, T. Regberg, M.R. Player, Tetrahedron Lett. 44 (1) (2003) 175] were described. The in vitro antimicrobial activity of the compounds was determined against some Gram-positive, Gram-negative bacteria, a fungi Candida albicans 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 250-7.81 microg/ml. While all compounds are less potent than fluconazole against C. albicans, most of them are more potent than fluconazole against C. albicans isolate.

In vitro and ex vivo activity of thioridazine derivatives against Mycobacterium tuberculosis.

Thioridazine (TZ) has previously been shown by us to have in vitro and ex vivo activity against antibiotic-susceptible and multidrug-resistant Mycobacterium tuberculosis (MDRTB). Because current therapy of MDRTB is highly problematic even when all five 'first line of defence' drugs are employed, there is a need for effective antituberculosis drugs. New derivatives of TZ were synthesised and their in vitro activity against a reference strain of M. tuberculosis was evaluated with the aid of the BACTEC 460 system. Derivatives that presented significant activity were evaluated by ex vivo studies and were shown to enhance the killing of intracellular M. tuberculosis.

Synthesis and biological evaluation of new N-(2-hydroxy-4(or 5)-nitro/aminophenyl)benzamides and phenylacetamides as antimicrobial agents.

A new series of N-(2-hydroxy-4(or 5)-nitro/aminophenyl)benzamide and phenylacetamide derivatives (1a-1n, 2a-2n) 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 compounds possessed a broad spectrum of activity against the tested microorganisms at MIC values between 500 and 1.95 microg/ml. Benzamide derivative 1d exhibited the greatest activity with MIC values of 1.95, 3.9, and 7.8 microg/ml against drug-resistant B. subtilis, B. subtilis, and S. aureus, respectively.

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 microM, 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.

Induction of apoptosis and necrosis by resistance modifiers benzazoles and benzoxazines on tumour cell line mouse lymphoma L5718 Mdr+cells.

Eighteen new fused heterocyclic compounds of benzazoles and benzoxazines were investigated for induction and inhibition of apoptosis on tumor cells (L5718, mouse lymphoma cell line containing the human mdr-1 gene). For evaluation of apoptosis, the cells were stained with FITC-labelled Annexin-V and propidium iodide and the results were analysed by flow cytometry. Nine of these substances were also checked for reversal of multidrug resistance. The reversal of multidrug resistance was determined by measuring the rhodamine-123 accumulation in the cancer cells. Rhodamine-123 shows a green fluorescence and its intracellular concentration correlates well with the inhibition of efflux pump activity. Three of the tested compounds, 5-(p-nitrobenzamido)-2-benzylbenzoxazole (BD-3), 6-methyl-2-(o-chlorophenyl) benzoxazole (A-9) and 5-(p-nitrophenoxyacetamido)-2-phenylbenzoxazole (D-30), showed an increased apoptotic effect on mouse lymphoma cells. Moreover, compounds BD-3, A-9 and 5-(2-thienylcarboxyamido)-2-phenylbenzoxazole (D-24) also amplified the apoptosis effect of 12H-benzo(a)phenothiazines (M-627). However, D-24, alone was not effective. Additionally, 2-(p-nitrobenzyl)benzoxazole (B-11), was also found to increase the apoptotic effect of M-627. On the other hand, 5-(p-nitrophenylacetamido)-2-phenylbenzoxazole (D-7) showed an anti-apoptotic effect. No positive correlation was found between the increased drug accumulation effect and the programmed cell death induced by the compounds studied.

3D-QSAR analysis on benzazole derivatives as eukaryotic topoisomerase II inhibitors by using comparative molecular field analysis method.

Selective topoisomerase II inhibitors have created a great deal of interest in recent years for the design of new antitumoral compounds. 3D-QSAR analysis has been performed on a series of previously synthesized benzoxazole, benzimidazole, and oxazolo(4,5-b)pyridine derivatives, which are screened as eukaryotic topoisomerase II inhibitors, using comparative molecular field analysis (CoMFA) with partial least squares fit to predict the steric and electrostatic molecular field interactions for the activity. The CoMFA study was carried out using a training set of 16 compounds. The predictive ability of the model was assessed using a test set of 7 compounds. The analyzed 3D-QSAR CoMFA model has demonstrated a good fit, having r(2) value of 0.997 and cross-validated coefficient q(2) value as 0.435 for the model. The obtained model reveals that the electronegatively charged substituents such as NO(2) or COOCH(3) group on position R and/or R(1) at the heterocyclic ring system and positively charged atom and/or atom groups located between the benzazole moiety and 2-substituted phenyl ring as a bridge element improve the activity. On the other hand, a bulky substituent, such as methoxy group, attached to the ortho position of 2-phenyl-5-nitro-benzoxazole (1) enhances the activity similar to compound 13, which is both a meta and para substituent of the phenyl group attached to the 2-position of benzimidazole ring system, fit into the favored steric region to improve the 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.

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.

A target site for template-based design of measles virus entry inhibitors.

Measles virus (MV) constitutes a principal cause of worldwide mortality, accounting for almost 1 million deaths annually. Although a live-attenuated vaccine protects against MV, vaccination efficiency of young infants is low because of interference by maternal antibodies. Parental concerns about vaccination safety further contribute to waning herd immunity in developed countries, resulting in recent MV outbreaks. The development of novel antivirals that close the vaccination gap in infants and silence viral outbreaks is thus highly desirable. We previously identified a microdomain in the MV fusion protein (F protein) that is structurally conserved in the paramyxovirus family and constitutes a promising target site for rationally designed antivirals. Here we report the template-based development of a small-molecule MV inhibitor, providing proof-of-concept for our approach. This lead compound specifically inhibits fusion and spread of live MV and MV glycoprotein-induced membrane fusion. The inhibitor induces negligible cytotoxicity and does not interfere with receptor binding or F protein biosynthesis or transport but prevents F protein-induced lipid mixing. Mutations in the postulated target site alter viral sensitivity to inhibition. In silico docking of the compound in this microdomain suggests a binding model that is experimentally corroborated by a structure-activity analysis of the compound and the inhibition profile of mutated F proteins. A second-generation compound designed on the basis of the interaction model shows a 200-fold increase in antiviral activity, creating the basis for novel MV therapeutics. This template-based design approach for MV may be applicable to other clinically relevant members of the paramyxovirus family.

Some fused heterocyclic compounds as eukaryotic topoisomerase II inhibitors.

Our previously synthesized 37 compounds, which are 2,5,6-substituted benzoxazole, benzimidazole, benzothiazole, and oxazolo(4,5-b)pyridine derivatives, were tested for their eukaryotic DNA topoisomerase II inhibitory activity in cell free system and 28 were found to inhibit the topoisomerase II at an initial concentration of 100 microg/ml. After further testing at a lower range of concentrations, 12 derivatives, which were considered as positive topoisomerase inhibitors, exhibited IC50 values between 11.4 and 46.8 microM. Etoposide was used as the standard reference drug to compare the inhibitor activity. Among these compounds, 2-phenoxymethylbenzothiazole (3f), 6-nitro-2-(2-methoxyphenyl)benzoxazole (1a), 5-methylcarboxylate-2-phenylthiomethylbenzimidazole (3c), and 6-methyl-2-(2-nitrophenyl)benzoxazole (1c) were found to be more active than the reference drug etoposide. Present results point out that, besides the very well-known bi- and ter-benzimidazoles, compounds with single bicycle fused ring systems in their structure such as benzimidazole, benzoxazole, benzothiazole, and/or oxazolopyridine derivatives also exhibit significant topoisomerase II inhibitory activity.

Synthesis and structure-activity relationships of new antimicrobial active multisubstituted benzazole derivatives.

A series of multisubstituted benzoxazoles, benzimidazoles, and benzothiazoles (5-7) as non-nucleoside fused isosteric heterocyclic compounds was synthesized and tested for their antibacterial activities against various Gram-positive and Gram-negative bacteria and antifungal activity against the fungus Candida albicans. Microbiological results indicated that the synthesized compounds possessed a broad spectrum of activity against the tested microorganisms at MIC values between 100 and 3.12 microg/ml. Structure-activity relationships (SAR) studies revealed that benzothiazole ring system enhanced the antimicrobial activity against Staphylococcus aureus. In these sets of non-nucleoside fused heterocyclic compounds electron withdrawing groups at position 5 of the benzazoles increased the activity against C. albicans.

Synthesis and HIV-1 reverse transcriptase inhibitor activity of some 2,5,6-substituted benzoxazole, benzimidazole, benzothiazole and oxazolo(4,5-b)pyridine derivatives.

In this study, the synthesis of some benzoxazoles and their analogues were described and their antiviral activities were studied together with the previously synthesized 2,5,6-trisubstituted benzoxazole, benzothiazole, benzimidazole and oxazolo(4,5-b)pyridine derivatives. The reverse transcriptase (RT) inhibitory activity of these compounds was determined using a commercial kit and assay system which utilizes the scintillation proximity assay principle. The results are concentration at which the compound inhibits RT activity by 50%). The compounds inhibited the in vitro binding of thymidine to the RT enzyme exhibiting IC50 values between 6.3 x 10(5) mumol/l-0.34 mumol/l and their activities were compared to some standard drugs such as 3'-azido-2',3'-dideoxythymidine triphosphate and dideoxythymidine triphosphate.

Synthesis and antimicrobial activity of some 2-[p-substituted-phenyl]benzoxazol-5-yl-arylcarboxyamides.

New 2-[p-substituted-phenyl ]benzoxazol-5-yl-arylcarboxyamides derivatives have been synthesized by reacting 5-amino-2-[p-substituted-phenyl ]benzoxazoles with substituted-arylcarboxylic 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 two-fold serial dilution technique against different Gram-positive and Gram-negative bacteria and the yeast C. albicans in comparison with standard drugs. Microbiological results indicated that the synthesized compounds possess a broad spectrum of activity, having an MIC value of 25-200 microg/mL at molar concentration values of 3.45 x 10(-5) and 5.74 x 10(-4) against the tested microorganisms.

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.