Benzoxazole Analogs Research Articles

Design, synthesis, and cytotoxicity of ibuprofen-appended benzoxazole analogues against human breast adenocarcinoma

A library of new ibuprofen-appended benzoxazole analogues (7a–l) was synthesized and screened for their in vitro anticancer activity against human breast cancer MCF-7 and MDA-MB-231 cell lines using doxorubicin as a standard reference.

Development and Characterization of Benzoselenazole Derivatives as Potent and Selective c-MYC Transcription Inhibitors.

Developing c-MYC transcription inhibitors that target the G-quadruplex has generated significant interest; however, few compounds have demonstrated specificity for c-MYC G-quadruplex and cancer cells. In this study, we designed and synthesized a series of benzoazole derivatives as potential G-quadruplex ligand-based c-MYC transcription inhibitors. Surprisingly, benzoselenazole derivatives, which are rarely reported as G-quadruplex ligands, demonstrated greater c-MYC G-quadruplex selectivity and cancer cell specificity compared to their benzothiazole and benzoxazole analogues. The most promising compound, benzoselenazole m-Se3, selectively inhibited c-MYC transcription by specifically stabilizing the c-MYC G-quadruplex. This led to selective inhibition of hepatoma cell growth and proliferation by affecting the MYC target gene network, as well as effective tumor growth inhibition in hepatoma xenografts. Collectively, our study demonstrates that m-Se3 holds significant promise as a potent and selective inhibitor of c-MYC transcription for cancer treatment. Furthermore, our findings inspire the development of novel selenium-containing heterocyclic compounds as c-MYC G-quadruplex-specific ligands and transcription inhibitors.

2‐Mercapto Benzoxazole Derivatives as Novel Leads: Urease Inhibition, In Vitro and In Silico Studies

AbstractTwenty‐three benzoxazole derivatives were prepared through two‐step reaction strategy. The precursor, 2‐mercapto benzoxazole was synthesized by reacting 2‐amino phenol with carbon disulfide in the presence of potassium hydroxide. Then, 2‐mercapto benzoxazole was further reacted with substituted phenacyl/benzyl bromide to afford a range of substituted 2‐mercapto benzoxazole analogs. All compounds were characterized by different spectroscopic techniques including mass spectrometry and nuclear magnetic resonance spectroscopy, and investigated against urease enzyme. All analogs revealed good to moderate urease inhibition, ranging from IC50 = 17.50±0.10 to 42.50±0.44 μM. Few derivatives showed superior activity than thiourea (IC50=21.50±0.47 μM), standard inhibitor of urease enzyme. Structure‐activity relationship (SAR) revealed the crucial participation of various structural features in the inhibitory process. Compounds bearing methoxy and halogen substituents were found to show more potency as compared with other molecules. Molecular docking showed various interesting interactions established by molecules (ligand) with the active pocket of urease enzyme.

An E. coli-Based Biosynthetic Platform Expands the Structural Diversity of Natural Benzoxazoles.

Benzoxazoles are frequently found in synthetic pharmaceuticals and medicinally active natural products. To facilitate benzoxazole-based drug development, an eco-friendly and rapid platform for benzoxazole production is required. In this study, we have completed the biosynthesis of benzoxazoles in E. coli by coexpressing the minimal set of enzymes required for their biosynthesis. Moreover, by coupling this E. coli-based platform with precursor-directed biosynthesis, we have shown that the benzoxazole biosynthetic system is highly promiscuous in incorporating fluorine, chlorine, nitrile, picolinic, and alkyne functionalities into the scaffold. Our E. coli-based system thus paves the way for straightforward generation of novel benzoxazole analogues through future protein engineering and combinatorial biosynthesis.

Benzothiazolyl substituted spiropyrans with ion-driven photochromic transformation

The present work is devoted to the synthesis and detailed investigation of new 8-benzothiazole containing spiropyrans. The investigated spiropyrans exist under colorless spirocyclic isomers exhibiting positive photochromism with thermo- and photoinduced back reaction. UV light irradiation leads to their effective coloration with quantum yields up to 44%. The efficiency of the back photocyclization induced by visible light does not exceed 0.1%. This feature distinguishes them from the previously studied benzoxazole analogs. The enhancement of electron-withdrawing properties of the indoline fragment substituents promotes an increase in photo-coloration efficiency. The lifetime of the colored form varies from 17 to 200.8 s (acetone, 293 K) depending on substituents. Due to the presence of the benzothiazole moiety, merocyanines can effectively bind Zn2+, Co2+, Ni2+, Cu2+, Cd2+, Mn2+ ions. The addition of salts of these ions to spiropyran solutions results in the stabilization of the merocyanine in the form of intensely colored complexes. Composition, stability and spectroscopic characteristics of complexes have been investigated depending on the metal ion nature and substituents in ligand molecules. The colored complexes possess negative photochromism. The visible light irradiation causes their bleaching with quantum yields up to 48%. The benzothiazole substituted spiropyrans demonstrate ion driving photochromic transformation.

Benzoxazole derivatives: design, synthesis and biological evaluation

BackgroundA new series of benzoxazole analogues was synthesized and checked for their in vitro antibacterial, antifungal and anticancer activities.Results and discussionThe synthesized benzoxazole compounds were confirmed by IR, 1H/13C-NMR, mass and screened for their in vitro antimicrobial activity against Gram-positive bacterium: Bacillus subtilis, four Gram-negative bacteria: Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Salmonella typhi and two fungal strains: Candida albicans and Aspergillus niger using tube dilution technique and minimum inhibitory concentration (MIC) was noted in µM and compared to ofloxacin and fluconazole. Human colorectal carcinoma (HCT116) cancer cell line was used for the determination of in vitro anticancer activity (IC50 value) by Sulforhodamine B assay using 5-fluorouracil as standard drug.ConclusionThe performed study indicated that the compounds 1, 10, 13, 16, 19, 20 and 24 had highest antimicrobial activity with MIC values comparable to ofloxacin and fluconazole and compounds 4, 6, 25 and 26 had best anticancer activity in comparison to 5-fluorouracil.

Design and synthesis of novel benzoxazole analogs as Aurora B kinase inhibitors

A novel series of benzoxazole analogs was designed and synthesized, and their inhibitory activities against Aurora kinases were evaluated. Some of the tested compounds exhibited a promising activity with respect to the inhibition of Aurora B kinase. A structure–activity relationship study indicated that linker length, regiochemistry, and halogen substitution play important roles in kinase inhibitory potency. The binding modes between representative compounds and Aurora kinases were interpreted through a molecular docking study to explain the inhibitory activity and selectivity for Aurora A and B kinases. Compounds 13l and 13q also show an antiproliferative effect on the human tumor cell lines in a dose-dependent manner. The most potent 13q demonstrated good efficacy in the prostate cancer PC-3 tumor xenograft model.

Synthesis and biological evaluation of benzoxazole fused combretastatin derivatives as anticancer agents

A series of ten novel benzoxazole analogues of combretastatin A-4 were designed, synthesized, and evaluated for their anticancer activity against three human cancer cell lines. Four of the synthesized compounds exhibited superior potency against different tumour cell lines. One of them showed more potent than control drug, particularly A549 and MCF-7 cell lines.

2-Amino-7-substituted benzoxazole analogs as potent RSK2 inhibitors

2-Amino-7-substituted benzoxazole analogs were identified by HTS as inhibitors of RSK2. Molecular modeling and medicinal chemistry techniques were employed to explore the SAR for this series with a focus of improving in vitro and target modulation potency and physicochemical properties.

Benzoheterocyclic amodiaquine analogues with potent antiplasmodial activity: Synthesis and pharmacological evaluation

The synthesis and evaluation of antiplasmodial activity of benzothiazole, benzimidazole, benzoxazole and pyridine analogues of amodiaquine is hereby reported. Benzothiazole and benzoxazole analogues with a protonatable tertiary nitrogen atom possessed excellent activity against the W2 and K1 chloroquine resistant strains of Plasmodium falciparum, with IC50s ranging from 7 to 22nM.

Identification of benzoxazole analogs as novel, S1P3 sparing S1P1 agonists

A novel series of benzoxazole-derived S1P1 agonists were designed based on scaffold hopping molecular design strategy combined with computational approaches. Extensive SAR studies led to the discovery of compound 17d as a selective S1P1 agonist (over S1P3) with high CNS penetration and favorable DMPK properties. 17d also demonstrated in vivo pharmacological efficacy to reduce blood lymphocyte in mice after oral administration.

Synthesis, metal ion binding, and biological evaluation of new anticancer 2-(2′-hydroxyphenyl)benzoxazole analogs of UK-1

UK-1 is a bis(benzoxazole) natural product displaying activity against a wide range of human cancer cell lines. A simplified analog of UK-1, 4-carbomethoxy-2-(2′-hydroxyphenyl)benzoxazole, was previously found to be almost as active as UK-1 against cancer cell lines, and similar to the natural product, formed complexes with a variety of metal ions such as Mg 2+ and Zn 2+. A series of 4-substituted-2-(2′-hydroxyphenyl)benzoxazole analogs of this ‘minimal pharmacophore’ of UK-1 were prepared. The anti-cancer activity of these analogs was examined in breast and lung cancer cell lines. Spectrophotometric titrations in methanol were carried out in order to assess the ability of UK-1 and these analogs to coordinate with Mg 2+ and Cu 2+ ions. Although none of the new analogs were more cytotoxic than 4-carbomethoxy-2-(2′-hydroxyphenyl)benzoxazole, some analogs were identified that display similar cytotoxicity to this simplified UK-1 analog with improved water solubility. UK-1 and all of these new analogs bind Cu 2+ ions better than Mg 2+ ions, and the nature of the 4-substituent is important for the Mg 2+ ion binding ability of these 2-(2′-hydroxyphenyl)benzoxazoles. Previous studies of a limited number of UK-1 analogs demonstrated a correlation between Mg 2+ ion binding ability and cytotoxicity; however, within this series of 4-substituted-2-(2′-hydroxyphenyl)benzoxazoles the variations in cytotoxicity do not correlate with either Mg 2+ or Cu 2+ ion binding ability. These results, together with recent ESI-MS studies of Cu 2+-mediated DNA binding by UK-1 and analogs, indicate that UK-1 and analogs may exert their cytotoxic effects by interaction with Cu 2+ or other transition metal ions, rather than Mg 2+, and that metal ion-mediated DNA binding, rather than metal ion binding affinity, is important for the cytotoxic effect of these compounds. The potential role of Cu 2+ ions in the cytotoxic action of UK-1 is further supported by the observation that UK-1 in the presence of Cu 2+ displays enhanced cytotoxicity to MCF-7 and A549 cells when compared to UK-1 alone.

Evaluation of Metal-Mediated DNA Binding of Benzoxazole Ligands by Electrospray Ionization Mass Spectrometry

The binding of a series of benzoxazole analogs with different amide- and ester-linked side chains to duplex DNA in the absence and presence of divalent metal cations is examined. All ligands were found to form complexes with Ni2+, Cu2+, and Zn2+, with 2:1 ligand/metal cation binding stoichiometries dominating for ligands containing shorter side chains (2, 6, 7, and 8), while 1:1 complexes were the most abundant for ligands with long side chains (9, 10, and 11). Ligand binding with duplex DNA in the absence of metal cations was assessed, and the long side-chain ligands were found to form low abundance complexes with 1:1 ligand/DNA binding stoichiometries. The ligands with the shorter side chains only formed DNA complexes in the presence of metal cations, most notably for 7 and 8 binding to DNA in the presence of Cu2+. The binding of long side-chain ligands was enhanced by Cu2+ and to a lesser degree by Ni2+ and Zn2+. The cytotoxicities of all of the ligands against the A549 lung cancer and MCF7 breast cancer cell lines were also examined. The ligands exhibiting the most dramatic metal-enhanced DNA binding also demonstrated the greatest cytotoxic activity. Both 7 and 8 were found to be the most cytotoxic against the A549 lung cancer cell line and 8 demonstrated moderate cytotoxicity against MCF7 breast cancer cells. Metal ions also enhanced the DNA binding of the ligands with the long side chains, especially for 9, which also exhibited the highest level of cytotoxicity of the long side-chain compounds.

Antiviral agents. 1. Benzothiazole and benzoxazole analogs of 2-(alpha-hydroxybenzyl)benzimidazole.

Antiviral agents. 1. Benzothiazole and benzoxazole analogs of 2-(alpha-hydroxybenzyl)benzimidazole.