Benzoxazole Derivatives Research Articles

Synthesis and Identification of some new Derivatives Oxazole, Thiazole and Imidazol from Acetyl Cysteine

Some fused heterocyclic oxazoles and imidazols rings were synthesized from reaction of N- acetyl cysteine with different treatment. After thiol group protection, N-acetyl-S-ethyl cysteine (2) had been esterified to give ester 3 which cyclized to oxazole 4 with phosphorus oxychloride. N-acetyl-S-ethyl cysteine 2 were converted to acid chloride 5 with thionyle chloride. Amide 6 were synthesized from 5 with ammonia solution. Amide 6 converted to substituted carbamide 7 by react with P2S5, then the product reacted with α-chloroacetophenone to give substituted thiazol ring 8 that converted to bicyclic thiazole – imidazole ring system 9. Cyclized benzoxazole derivative 10 had been synthesized then converted to 3-(ethylthio)-1-methyl-1,3a-dihydrobenzo[d]imidazo[5,1-b]oxazole (11). Structure of new synthesized compounds were confirms by IR ,1H-NMR, and UV spectra as well as physical constant.

One-Pot Multicomponent Coupling Reaction of Catechols, Benzyl Alcohols/Benzyl Methyl Ethers, and Ammonium Acetate toward Synthesis of Benzoxazoles.

The multicomponent coupling reaction of catechol, ammonium acetate, and benzyl alcohol/benzyl methyl ether in the presence of a Fe(III) catalyst precursor afforded benzoxazole derivatives in good to excellent yields. The notable features of this protocol are abundant availability of the catalyst system, large-scale synthesis, high diversity, and high yields of products.

A Patent Review on the Current Developments of Benzoxazoles in Drug Discovery.

The benzoxazole moiety is widely found in various natural compounds, which are often found to be biologically active. Due to its versatile biological properties, benzoxazole has been incorporated as an essential pharmacophore and substructure in many medicinal compounds. In the past years, numerous benzoxazole derivatives have been synthesised and evaluated for their biological potential. The wide range in therapeutic potential of benzoxazole derivatives is related to the favourable interactions of the benzoxazole moiety with different protein targets. Herein we review the biological activities of benzoxazole derivatives patented within the past six years. Using the Lens database, granted patents issued from 2015 to 2020 were retrieved. The patented benzoxazole derivatives demonstrated excellent activity against various protein targets and diseases, with some reaching clinical trial stage. Pharmacological and medicinal aspects of patented benzoxazole derivatives are discussed. The recent development and drawbacks are also reviewed.

In Vitro Anti-Candida Activity and Action Mode of Benzoxazole Derivatives.

A newly synthetized series of N-phenacyl derivatives of 2-mercaptobenzoxazole, including analogues of 5-bromo- and 5,7-dibromobenzoxazole, were screened against Candida strains and the action mechanism was evaluated. 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(4-bromophenyl)ethanone (5d), 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(2,3,4-trichloro-phenyl)ethanone (5i), 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(2,4,6-trichlorophenyl)ethanone (5k) and 2-[(5-bromo-1,3-benzoxazol-2-yl)sulfanyl]-1-phenylethanone (6a) showed anti-C. albicans SC5314 activity, where 5d displayed MICT = 16 µg/mL (%R = 100) and a weak anti-proliferative activity against the clinical strains: C. albicans resistant to azoles (Itr and Flu) and C. glabrata. Derivatives 5k and 6a displayed MICP = 16 µg/mL and %R = 64.2 ± 10.6, %R = 88.0 ± 9.7, respectively, against the C. albicans isolate. Derivative 5i was the most active against C. glabrata (%R = 53.0 ± 3.5 at 16 µg/mL). Benzoxazoles displayed no MIC against C. glabrata. Benzoxazoles showed a pleiotropic action mode: (1) the total sterols content was perturbed; (2) 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(3,4-dichlorophenyl)ethanol and 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(2,3,4-trichlorophenyl)ethanol (8h–i) at the lowest fungistatic conc. inhibited the efflux of the Rho123 tracker during the membrane transport process; (3) mitochondrial respiration was affected/inhibited by the benzoxazoles: 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(4-chlorophenyl)ethanol and 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(4-bromophenyl)ethanol 8c–d and 8i. Benzoxazoles showed comparable activity to commercially available azoles due to (1) the interaction with exogenous ergosterol, (2) endogenous ergosterol synthesis blocking as well as (3) membrane permeabilizing properties typical of AmB. Benzoxazoles display a broad spectrum of anti-Candida activity and action mode towards the membrane without cross-resistance with AmB; furthermore, they are safe to mammals.

Synthesis, Antimicrobial evaluation and Docking study of new Schiff bases of benzo[d]oxazol-5-amine derivatives.

Objective: Benzoxazole derivatives have antifungal, anticancer, antibacterial, and anticonvulsant function. Encouraged by this comment, we agreed to synthesize new Benzoxazole compounds connected to the bases of Schiff's. Methods: 2,4-diaminophenol (1) was prepared by the reaction of 2,4-dinitrophenol and sodium dithionate. Compound (1) reacted with either acetic acid to afford compound (2) or with formic acid to afford compound (3). The Schiff bases were preparation from the reaction condensing reaction of compound (2) or (3) and aromatic aldehydes or ketone; [p-nitrobenzaldehyde, p-hydroxybenzaldehyde, p-chlorobenzaldehyde, p-bromoacetophenone and terephthaldehyde]. Results: FTIR and 1H-NMR spectroscopy characterized all of the preparation compounds. The synthesized derivatives against (Gram positive bacteria GPB) (Bacillus subtilis) and two (Gram-negative bacteria GNB) (Klebsiella pneumoniae and Escherichia coli) and (one fungal species Candida albicans), have been evaluated to their antibacterial activity in vitro. all results showed which most of them have good antibacterial activity, while their antifungal activity revealed that compounds displayed slight antifungal activity. The synthesized Benzoxazole derivatives were docked using, glucosamine 6-phosphate synthase as a ligand. Conclusion: The antimicrobial activity indicates that compounds (4), (7) and (8) have more potent antibacterial activity than the compounds (5) and (6). Molecular docking study revealed that compounds (7) and (8), with bulky phenyl groups are essential to block the active centers of (GluN-6-Ps) amino acids synthase in the bacteria.

A New Method for the Synthesis of 2-Substituted Benzoxazoles from 2-Nitrophenol Derivatives and Aldehydes

Benzoxazole derivatives are one of the compounds with many interesting biological activities. Conventional methods are often performed under complex conditions using strong acids, expensive metal catalysts, requiring high pressure, high temperature, and under microwave irradiation. In this study, we reported a new method of benzoxazole synthesis with redox catalyst using FeCl3.6H2O and sulfur. This is a suitable, efficient, readily available and environmentally friendly catalyst system for redox and condensation reactions in one step at 100 oC. Applying this new method, we have synthesized eight 2-arylbenzoxazole derivatives with high yields (calculated according to 2-nitrophenol). This research is an important step forward in the synthesis of biologically active compounds containing the benzoxazole framework from readily available starting materials in a single reaction.

Synthesis, quantum mechanical calculations, antimicrobial activities and molecular docking studies of five novel 2,5-disubstituted benzoxazole derivatives

In this study, five new 2-(p-(Substituted)phenyl)-5-(3-(4-ethylpiperazine-1-yl) propionamido)benzoxazole derivatives (B7-B11) were designed, synthesized, and their antimicrobial activities were determined by the microdilution method. The novel benzoxazole compounds were characterized using FTIR, 1H NMR, and 13C NMR spectroscopy, mass spectroscopy, and elemental analysis. B7 and B11 showed promising activity against P. aeruginosa isolate at 16 µg/mL compared to the reference drugs. Quantum mechanical calculations were performed on five compounds in the ground state using density functional theory (DFT) with the B3LYP/6–311G(d,p) level. Molecular docking studies of the compounds were also performed a complex structure of the DNA gyrase enzyme with ciprofloxacin (PDB: 2XCT), and it was observed that the binding poses were similar to ciprofloxacin. Theoretical ADME profiles of the compounds conform to Lipinski and other limiting rules.

2-(2-(Fluorosulfonyloxy)phenyl)benzoxazole

The fluorosulfate derivatives of benzoxazole attract attention since benzoxazole-based compounds have a wide range of biological activities, and the ability of the –SO2F group to react with various functional groups makes it possible to synthesize various new derivatives. The new 2-(2-(fluorosulfonyloxy)phenyl)benzoxazole (2) has been synthesized by the SuFEx click reaction in a two-chamber reactor. Compound 2 is the first example of a benzoxazole derivative with a fluorosulfate-containing substituent at position two of the benzoxazole heterocycle. The anti-cancer potency of 2 was evaluated in silico using molecular docking. The docking results suggest that title compound 2 is of great interest for further studies as a possible anaplastic lymphoma kinase inhibitor.

The reported formation of 5H‐dibenzo[b,e][1,4]diazepin‐11(10H)‐ones in the noncatalyzed, base‐promoted double arylation of anthranilamide revisited. Correction of some product structures

AbstractThe base‐promoted reaction of 2‐halonitro‐ or 1,2‐dihalobenzenes with anthranilamide reported by Cao, Ma et al. (Synthesis 2013, 45, 111) was reinvestigated. Some of the products reported, which have been identified as dibenzodiazepinones, are actually benzoxazole derivatives. In this paper, the correct structures of these products were established and confirmed by independent synthesis. For four other products, the supposed structures were found to be incompatible with the dibenzodiazepinones that were synthesized by the reliable method used in this work.

Synthesis, biological evaluation and molecular docking studies of heterocycle encompassed benzoxazole derivatives as antimicrobial agents

Novel heterocycles containing benzoxazole nucleus have been synthesized from ethoxy cyano acrylate. All the synthesized molecules were subjected to structural elucidation using spectrometric and spectroscopic characterization using analytical proton NMR (1H), carbon NMR (13C), Fourier transform Infrared spectroscopy (FT-IR) and Liquid chromatography Mass spectrometry. In silico docking studies were carried out to investigate the structural insights into the binding mode to evaluate antimicrobial potency. The docking results against the X-ray crystallographic structure of Staphylococcus aureus UDP-N-acetylenolpyruvylglucosamine reductase (MurB) (PDB ID: 1HSK) protein have shown minimum binding energy of −6.1, −7.6, −7.1, −7.8, and −8.2 for 1A, 2A, 3A, 4A, and 4B molecules respectively. Among which, 4A and 4B molecules have evolved as potential antimicrobial agents from initial screening of the molecules against fungi, gram-positive, and gram-negative bacteria using the agar well diffusion method and minimum inhibition concentration technique.

Synthesis and Molecular Docking Studies of Potent Urease Inhibitors Based on Benzoxazole Scaffold

AbstractIn this study, we report the synthesis, in silico molecular docking, and in vitro urease inhibition studies of a novel series of benzoxazole derivatives. The title compound in the series namely (2‐(benzo[d]oxazol‐2‐ylthio)‐1‐(4‐substitute‐phenyl)ethan‐1‐one oxime was synthesized by the reaction of 2‐aminophenol with different kinds of intermediates in several steps through both conventional and microwave techniques. All compounds were found to have an excellent degree of urease inhibitory potential ranging from 0.46±0.01 to 46.10±0.45 μM in compared with standard inhibitor acetohydroxamic acid with IC50 320.70±4.24 μM. Structure‐activity relationship was established in detail. In addition, we confirmed the binding interactions of compounds with enzymes using molecular docking.

Synthesis and properties of benzoxazole-terminated mesogenic compounds containing tolane with high birefringence and large dielectric anisotropy

ABSTRACT New benzoxazole-terminated mesogenic compounds containing tolane moiety with high birefringence and large dielectric anisotropy, namely, 2-[4-[2-[4-alkoxyphenyl]ethynyl]-2,6-difluoro-phenyl]-benzoxazole derivatives (nPEDFPBx), were synthesised and investigated. Among them, the ones bearing methyl and nitro substituents at 5-position of benzoxazole moiety exhibit stable mesophase ranges of 30–71°C and 55–81°C during heating and cooling processes, respectively, while the non-substituted compounds exhibit no mesophase except the ones with long terminal alkoxy chain (n = 10, 12). Birefringence of nPEDFPBx is obtained from DFT theoretical calculation (0.446–0.583) and experimental measurement (0.395–0.499), respectively, where high birefringence is ascribed to their large π-conjugated molecule composed of benzene ring, acetylene linkage and benzoxazole moiety. Meanwhile, it is found that nPEDFPBx displays large dielectric anisotropy because of their high dipole moment. As an example, the compound 5PEDFPBM is doped into the liquid crystalline mixture as an additive, the properties of the resulting mixture, such as birefringence, dielectric anisotropy, clearing point and response time, are improved obviously, indicating high potential application for liquid crystalline mixture.

DFT, docking, MD simulation, and vibrational spectra with SERS analysis of a benzoxazole derivative: an anti-cancerous drug

Spectroscopic, DFT, and SERS studies of antimicrobial bioactive 2-(p-bromophenyl)-5-(2-(4-(p-chlorophenyl)piperazine-1-yl)acetamido)benzoxazole (BCAB) have been reported. Very large changes are seen wavenumbers in Raman and SERS. Variations in modes may be due to surface π-electron interactions and means, the BACB is inclined with respect to the metal surface. Theoretical molecular geometry optimization parameters, wavenumbers, frontier molecular orbitals, and molecular electrostatic potential surface have been calculated using density functional theory. The docked ligand forms a stable complex with SOCS-2 and can be BCAB may be an anti-cancerous drug. According to RMSD, RMSF, and Rg analysis, BACB and SOCS-2 protein form a stable and stable interaction.

Synthesis, antimicrobial activity, density functional modelling and molecular docking with COVID-19 main protease studies of benzoxazole derivative: 2-(p-chloro-benzyl)-5-[3-(4-ethly-1-piperazynl) propionamido]-benzoxazole

This study contains synthesis, antimicrobial activity, density functional modelling and molecular docking studies of benzoxazole derivative: 2-(p-chloro-benzyl)-5-[3-(4-ethly-1-piperazynl) propionamido]-benzoxazole. The synthetic procedure of investigated compound is given in detail. The newly synthesized benzoxazole compound and standard drugs were evaluated for their antimicrobial activity against some Gram-positive, Gram-negative bacteria and fungus C. albicans and their drug-resistant isolates. The benzoxazole compound has been characterized by using 1H-NMR, IR and MASS spectrometry and elemental analysis techniques. The molecular structure of the compound in the ground state has been modelling using density functional theory (DFT) with B3LYP/6-311++g(d,p) level. The molecular docking of 2-(p-chloro-benzyl)-5-[3-(4-ethly-1-piperazynl) propionamido]-benzoxazole with COVID-19 main protease has been also performed by using optimized geometry and the experimentally determined dimensional structure of the main protease (M-pro) of COVID-19.

Structure of Biologically Active Benzoxazoles: Crystallography and DFT Studies

Using X-ray single crystal diffraction, the crystal structures of biologically active benzoxazole derivatives were determined. DFT calculation was performed with standard 6-31G*(d), 6-31G** and 6-31+G* basis set to analyze the molecular geometry and compare with experimentally obtained X-ray crystal data of compounds. The calculated HOMO-LUMO energy gap in compound 2 (2-(2-hydroxynaphtalen-1-yl)-4-methyl-7-isopropyl-1,3-benzoxazol-5-ol) is 3.80 eV and this small gap value indicates that compound 2 is chemically more reactive compared to compounds 1 (4-methyl-2-phenyl-7-isopropyl-1,3-benzoxazol-5-ol) and 3 (2-(4-chlorophenyl)-4-methyl-7-isopropyl-1,3-benzoxazol-5-ol). The crystal structures are stabilized by both intra- and intermolecular hydrogen bonds in which an intermolecular O-H⋅⋅⋅N hydrogen bond generates N3 and O7 chain motif in compounds 1, 2, and 3, respectively. The calculated bond lengths and bond angles of all three compounds are remarkably close to the experimental values obtained by X-ray single crystal diffraction.

Synthesis of Benzoxazole‐2‐carboxylate Derivatives: Electronic‐ and Position‐effect of Functional Groups and Computational Modeling of the Selectivity for Oxazole Ring

AbstractIn this study, Mitsunobu reagent, DEAD (diethyl azodicarboxylate) and PPh3, and ethyl‐oxalamide derivatives of 2‐aminophenol were reacted under mild reaction conditions. As a result of the cyclization reaction, benzoxazole derivatives bearing an ester group in the C‐2 position were obtained in a one‐pot protocol. It was observed that the electron‐donating groups at the C‐5 position and the electron‐withdrawing groups at the C‐6 position of the benzene ring increased the yield of the cyclic product. It was found that the cyclization does not occur when the carboxylic acid group is substituted in the benzene ring. The cyclization reaction we performed preferred the 5‐endo‐trig reaction instead of the 6‐exo‐trig. This experimental result was examined in detail with density functional theory (DFT) calculations as well. A computational exploration is presented herein that elucidates the detailed mechanism for Huisgen zwitterion‘s reaction with ethyl‐oxalamide derivatives of 2‐aminophenol. Potential alternative mechanisms were modeled with DFT calculations via CPCM/M06‐2X/6‐311++G(d,p)//B3LYP/6‐31+G(d,p) level method in tetrahydrofuran to understand shed light on the mechanism. Our computational results are in good agreement with experimental findings that benzoxazole derivatives are the sole products in this reaction.

New Benzoxazole Derivatives as Antiprotozoal Agents: In Silico Studies, Synthesis, and Biological Evaluation

Background. Benzoxazole derivatives have different biological activities. In pursuit of designing novel chemical entities with antiprotozoal and antimicrobial activities, benzoxazolyl aniline was utilized as a privileged scaffold of a series of (3-benzoxazole-2-yl) phenylamine derivatives, 3-benzoxazoloyl acetamide, and butyramide derivatives. Methods. These novel analogs were synthesized in straightforward simple chemistry without any quantitative chromatographic separations in reasonable yields. The biological evaluation of all target compounds as potential antimalarial, antileishmanial, antitrypanosomal, and antimicrobial agents was performed by various well-established cell-based methods. Results. Compounds 6d and 5a showed promising biological screening data. The amidation of 3-benzoxazolyl aniline 1 with the chloroacetyl functional group resulted in a good antimalarial activity and showed moderate inhibitory activities against leishmanial and trypanosomal spp. Moreover, chloroacetyl functionalization of benzoxazolyl aniline serves as a good early goal for constructing and synthesizing new antimicrobial and antiprotozoal agents. The molecular docking study rationalizes the relative inhibitory activity of compound 5a as an antimalarial agent with the deregulation of PfPNP activity which has emerged as a major mechanism of these targets.

Synthesis, Molecular Docking, Molecular Dynamics, DFT and Antimicrobial Activity Studies of 5-substituted-2-(p-methylphenyl)benzoxazole Derivatives

In this study, new 2-(p-methylphenyl)-5-(2-substitutedacetamido)benzoxazole derivatives were synthesized, and antimicrobial activities on six bacteria and their twelve drug-resistant isolates and one fungus and its two drug-resistant isolates were investigated by microdilution method. B1 against Staphylococcus aureus isolate, and B1 and B2 against Escherichia coli isolate showed more potent antimicrobial activity with MIC value of 16 µg/mL than some of the reference drugs. The compounds' interactions on the DNA gyrase enzyme were evaluated by molecular docking and molecular dynamics simulations. Docked compounds have demonstrated superimposition in the DNA gyrase ATP binding site with similar protein-ligand interactions. With 50 ns duration molecular dynamics simulations, the average RMSD value of the DNA gyrase subunit B protein and B1, B2, B3, and B4 complexes were measured at about 0.15 nm. The ligands-bound DNA gyrase subunit B protein is a little less RMSF value and more stable than the apoprotein form between 45-49 residues in the active site amino acids region. Geometric optimization parameters, HOMO-LUMO orbital energies, and other electronic parameters derived from these energies, MEP, and NBO analysis were performed the DFT/B3LYP theory and 6-311G (d,p) basis set. The ΔE: LUMO-HOMO of the two most active compounds B1 and B2 are 4.2928 and 4.3219, respectively. The compounds' predicted ADME profiles were in line with Lipinski and other limiting rules.

Antiproliferative activity, enzymatic inhibition and apoptosis-promoting effects of benzoxazole-based hybrids on human breast cancer cells

New benzoxazole derivatives containing 1,3,4-oxadiazole, 1,2,4-triazole or triazolothiadiazine rings were synthesized and screened for their in vitro antiproliferative activities against MCF-7 and MDA-MB-231 breast cancer cell lines using MTT assay. Doxorubicin, cisplatin and 2-(4-aminophenyl)benzothiazole (CJM 126) were used as references. The most active compounds 7a, 8d, 8e and 10c were screened for their antiproliferative activities against MCF-10A normal breast cells where compounds 8e and 7a were the most selective towards MCF-7 and MDA-MB-231 cell lines, respectively compared to CJM 126. In vitro enzymatic inhibition assays of epidermal growth factor receptor (EGFR) and aromatase (ARO) enzymes were performed. Compound 7a showed inhibition of EGFR comparable to that of erlotinib while compound 8e exhibited nearly half the inhibitory activity of erlotinib towards EGFR and was more potent inhibitor of ARO than letrozole. Caspase-9 activation assay, cell cycle analysis and Annexin–V/ Propidium iodide assay performed for compounds 7a, 8d, 8e and 10c demonstrated over expression of caspase-9 protein level, pre G1 apoptosis and high annexin V binding affinity. Therefore, these compounds are considered as potent apoptosis-promoting agents. The predicted docking studies and in silico chemo-informatic properties of compounds 7a and 8e were appropriate. Compounds 7a and 8e are promising anti-breast cancer agents exhibiting potent apoptosis-promoting properties.

Synthesis of bis(benzoxazole) frameworks chiralized by planar chiral [2.2]Paracyclophane

In this study, a new class of chiral bis(benzoxazole) has been synthesized. The bis(benzoxazole) framework, which has an achiral structure was chiralized by a planar chiral [2.2]paracyclophane moiety. Both enantiomeric forms of the bis(benzoxazole) derivatives were successfully obtained in 99% ee. Even though the starting material was not completely enantiomerically pure, enantiomeric enrichment was afforded by the Horeau principle in the synthesis route.