Benzo[b][1,4]oxazines constitute an important scaffold in synthetic organic chemistry in terms of having special applications in drug discovery and bioactive compounds. Thus, finding new methods for their synthesis is of high importance. In the present study, we have synthesized 2H-benzo[b][1,4]oxazine-3-carboxamide derivatives through a one-pot sequence of SN cyclization-Ugi reaction in ionic liquid, [emim][BF4], as the reaction solvent. Thus, a series of five novel derivatives of the target structure were obtained in 74%–80% yields via a four-component procedure. It was observed that the efficiency of the process under [emim][BF4] conditions is improved in comparison to the conventional Ugi reaction in MeOH medium.
A series of 5-methoxy aryl benzimidazole derivatives were designed and synthesized using a simple two-step facile method. The novel benzimidazole derivatives were characterized through FT-IR, H-1-NMR,C-13-NMR, and LC-MS. The synthesized compounds (C1-C9) were screened for their in vitro anticancer activity against MCF-7 (human breast adenocarcinoma), HeLa (cervical cancer), and A549 (non-small-cell lung carcinoma) cell lines using cell viability assays. These cell lines exhibit high basal surface expression of EGFR, the cytotoxic effects were evaluated over a broad concentration range (0.625 to 300 & micro;g/mL), and the IC50 values were determined. Doxorubicin was used as a standard reference drug for comparison. In the designed 5-methoxy aryl benzimidazole derivatives, C1 and C7 were the top hits in molecular docking. They had better interaction than the standard reference, with interaction energies of -9.280 and -9.250 kcal/mol, respectively. They had hydrogen bond interactions with THR798 and MET801 at the ATP-binding site of EGFR kinase. Among the tested compounds, C7 and C1 demonstrated significant anticancer activity, showing potent growth inhibition with an IC50 value of 9.2 +/- 0.5 & micro;M against the MCF-7 cell line, highlighting its potential as a strong candidate for breast cancer therapy. Similarly, Compound C1 demonstrated notable potency against the A549 cell line, with an IC50 value of 16.6 +/- 2.3 & micro;M. These novel 5-methoxy aryl benzimidazole derivatives exhibited potent anticancer activity.
A bionic superhydrophobic method was conducted by combining hydrophobic modification of three-dimensional (3D) and two-dimensional (2D) materials with surface nanostructure regulation. Polydimethylsiloxane (PDMS)-modified nanosilica (SiO2) was utilized with heteroatom-functionalized aminosilane (KH550) as a key coupling agent to prepare a uniformly dispersed PDMS/SiO2 composite solution, which was then coated onto 3D polyurethane (PU) foam and 2D cellulose membranes (CF) to mimic the "lotus leaf" micro-nano papillary structure. A homogeneous nanoscale rough surface was achieved on the modified material, with a water contact angle of 152.3 degrees and an oil contact angle approaching 0 degrees, demonstrating exceptional superhydrophobicity and superoleophilicity. Separation experiments indicated selective adsorption of organic solvents typical in pharmaceutical processes, with a dichloromethane adsorption capacity of 21.07 g/g. After 10 adsorption-squeezing cycles, the material retained over 85% of its initial adsorption capacity, highlighting its durability. This study provides a cost-effective and environmentally friendly approach for developing high-efficiency materials for the removal and recovery of organic solvents from aqueous streams in pharmaceutical manufacturing and wastewater treatment.
A convenient approach for the synthesis of 2-acetyl-4-phenylquinoline designed monospiro-pyrrolidine/thiapyrrolizidine hybrids has been achieved via a 1,3-dipolar cycloaddition reaction of various azomethine ylides derived from isatin/acenaphthylene-1,2-dione/ninhydrin, ortho -phenylenediamine and sarcosine/ L -4-thiazolidinecarboxylic acid with 2-acetyl-4-phenylquinoline chalcone derivatives as dipolarophile. The regio- and stereochemistry of formation of the cycloadducts were determined by proton, carbon and 2D NMR and HR-MS techniques. Additionally, the formation of products based on the secondary orbital interaction mechanism and intrinsic reaction coordinate calculation (HOMO and LUMO) on the proposed TS structure was unambiguously confirmed by the density functional theory using the B3LYP/6-311G(d,p) levels of theory.
Owing to the remarkable physical properties and versatile chemistry of germanium, the synthesis of ruthenium-germylene compounds offers broad application potential and addresses important practical demands. In this study, we explored the substitution reactivity of germylene ligands both prior to and following coordination to transition metals. Using the ferrocenylacetylene-supported germylene FcC equivalent to CGe(NArCMe)2CH (1, Fc = (eta 5-C5H4)Fe(eta 5-C5H5)) as a precursor, the bis(germylene)-coordinated ruthenium complex Ru(CO)3[FcC equivalent to CGe(NArCMe)2CH]2 (2, Ar = 2,6-iPr2C6H3) was synthesized. Treatment of the carbonyl-ruthenium-germylene compound Ru(CO)3[ClGe(NArCMe)2CH]2 (3) with a reducing agent, followed by workup, afforded a novel ruthenium-germylene complex, Ru(CO)4[(OH)Ge(NArCMe)2CH] (4). In this species, the chlorine atom bound to germanium is replaced by a hydroxyl group, and only a single germylene ligand coordinates to the ruthenium center. In contrast, the reaction of complex 3 with tricyclohexylphosphine (PCy3) yielded the previously reported compound Ru(PCy3)2(CO)3 (5). The molecular structures of complexes 2 and 4 were confirmed by X-ray crystallography and spectroscopic analyses, while the structure of 5 was verified by comparison with literature data.
The promising approach toward the synthesis of novel sulfur-based quinoline and benzoquinoline isostere molecules. The condensation reaction involves 4-chloro-2,8-dimethylquinolines or 4-chloro-2-methylbenzo[h]quinoline and corresponding o-thiosalicylic acid and 2-mercaptonicotinic acid, either in ethanol (as a solvent) or under solvent-free (neat) conditions. This results in the formation of an intermediate, which yields significantly better results when using neat solvent-free conditions. The intermediates then undergo cyclization using polyphosphoric acid (PPA). Notably, the sulfur-based quinoline and benzoquinoline isosteres are prepared through a highly efficient one-pot methodology using CuI/Cs2CO3/DMSO conditions, which yields higher than the PPA condition through a step-by-step method. The synthesized novel sulfur-containing isosteres are further analyzed through quantum chemical calculations of the frontier molecular orbitals (FMOs) and molecular electrostatic potential (MEP) using the M06-2X method with a 6-311 + G (d, p) basis set in water. Additionally, in silico analyses are performed in detail to predict the potential biological activity of the synthesized molecules through molecular docking and MM-GBSA analysis against the CDK8/CycC complex. Furthermore, ADME parameters have been analyzed, and all the final cyclized molecules show the most promising drug-like properties, inspiring further research in medicinal chemistry.
An unsymmetrical salen-type Schiff base ligand, (Z)-1-(((2-((E)-(2-hydroxy-6-methoxybenzylidene)amino)phenyl)amino)methylene)naphthalen-2(1H)-one, and its Zn(II), Cu(II), Co(II), Mn(II), and Fe(III) complexes were synthesized and characterized by mass (MS), nuclear magnetic resonance (NMR), infrared (IR), ultraviolet-visible (UV-Vis) spectra, and effective magnetic moments. The thermal analyses of the obtained ligand and metal complexes were conducted by thermogravimetric analysis (TGA). Antimicrobial activity of the unsymmetrical Schiff base ligand and its metal complexes were examined for Staphylococcus aureus as Gram-positive bacteria and Escherichia coli as Gram-negative bacteria. In vitro anticancer property of synthetic compounds was estimated against human cancer cell lines, a subline of Hela tumor cell line (KB), and a human liver cancer cell line (HepG-2) as well.
A series of 2,3-dihydro-1,5-benzodiazepine derivatives have been synthesized and characterized using IR, NMR, GC-MS, single crystal XRD, and microanalysis. The results of their antibacterial activity against methicillin-resistance Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Bacillus subtilis, Streptococcus mutans, Pseudomonas aeruginosa, Salmonella typhi, and Streptococcus pyrogens indicated that most of the compounds were bacteriostatic (0.125−4 mg/mL) and also exhibited good biofilm inhibition (0.21−72.69%). The compounds were found to be synergistic when used in combination with other antibiotics. The antiproliferative and cytotoxic effects were also investigated against PC-3 prostate cancer and RAW 264.7 macrophage cell lines, respectively, using the MTT assay. Apart from compounds 6 and 7, a good number of the compounds (1, 2, 3, 4, 5, and 8) were selectively toxic to the prostate cancer cells at 20 µM, whilst sparing the normal cells. Compound 3 demonstrated the highest antiprostate cancer effect by reducing the viability of PC-3 cells to (13.75%), which was followed by compounds 1 (47.72%), 2 (48.18%), 4 (62.61%), 5 (66.70%), and 8 (69.55%).
Eleven conjugates between dihydroartemisinin (DHA) with thiols containing both ether and thioether bonds were designed, synthesized by a two-step procedure including etherification and S-alkylation. Analysis of the NMR spectral data indicated that the dimer of DHA with thiols 6-mercaptopurine and 2-mercaptoimidazole was produced with yields of 31% and 62%, respectively. Furthermore, the tautomerization of thiol 5-methoxy-2-mercaptobenzimidazole led to the formation of a mixture of two isomers in which they might be interchangeable through a dynamic tautomeric equilibrium in the solution. Screening in vitro biological activities revealed that most of the synthesized conjugates showed good cytotoxic and anti-inflammatory activity, while three of them displayed α-glucosidase inhibitory activity. Notably, two conjugates 5d and 5e of DHA with thiols 2-mercaptopyrimidine and 2-mercaptobenzothiazole had an effect in all tested activities in which conjugate 5e is the most potent.
Two isopropyl (3-methyl-1-oxo-1-((1-((4-(prop-2-yn-1-yloxy)phenyl)thio)propan-2-yl)amino)butan-2-yl)carbamate diastereomers were isolated. Fungicidal activities indicated that the isolated four chiral compounds possessed excellent activity against P. capsici with the EC 50 value of 4a (1.30 μ g/mL), 4b (0.078 μ g/mL), 4c (1.85 μ g/mL), and 4d (44.4 μ g/mL). Among them, compound 4b exhibited remarkably high activities against Phytophthora capsici , which is better than that of positive control dimethomorph. Its R and S isomers showed that chiral influences the activity against P. capsici .
A library of six compounds with new hybrids in a single molecule triazole ring attached to the phosphonium salts was synthesized. Click chemistry was, however, used to synthesize the 1-, 2-, and 3-triazole intermediates as a tether for the hybrid phosphonium salts. Their antibacterial activity against Gram-positive bacteria (Staphylococcus aureus and Enterococcus faecalis), Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa), and Mycobacterium smegmatis mc2155 was determined using the HT-SPOTi assay. Compound 2 showed the most effective antimicrobial activity as it inhibited the growth of Pseudomonas aeruginosa and Staphylococcus aureus at 0.0125 µg/mL and 31.25 µg/mL, respectively. From the FICI data, compounds 2ET-TOL (2) and RABYL-TOL (4) successfully modulated the activities of amoxicillin against Pseudomonas aeruginosa and Staphylococcus aureus. All the test compounds exhibited a concentration-dependent biofilm formation inhibition against S. aureus, except P-Z (compound 6). Compounds P-MEOXY (1) and 2ET-TOL (2) exhibited mild activity against P. aeruginosa with compound 4 showing antimycobacterial activity at 500 µg/mL.
Two isopropyl (3-methyl-1-oxo-1-((1-((4-(prop-2-yn-1-yloxy)phenyl)thio)propan-2-yl)amino)butan-2-yl)carbamate diastereomers were isolated. Fungicidal activities indicated that the isolated four chiral compounds possessed excellent activity against P. capsici with the EC50 value of 4a (1.30 μg/mL), 4b (0.078 μg/mL), 4c (1.85 μg/mL), and 4d (44.4 μg/mL). Among them, compound 4b exhibited remarkably high activities against Phytophthora capsici, which is better than that of positive control dimethomorph. Its R and S isomers showed that chiral influences the activity against P. capsici.
Fifteen new pyrazole-4-carboxylic oxime ester derivatives were conveniently synthesized, and their structures were confirmed by 1H NMR, 13C NMR, HRMS, and X-ray diffraction. Antifungal assays indicated that some of these compounds possessed good activity against S. sclerotiorum, B. cinerea, R. solani, P. oryae, and P. piricola at 50 ppm. Structure-activity relationships (SAR) were studied by molecular docking simulation.
In the last few years, nonsteroidal aromatase inhibitors (AIs) have been emerged as promising agents for treating hormone-dependent breast cancer in postmenopausal women because of their inhibitory effect on estrogen synthesis. Indeed, these compounds can block the activity of aromatase, the enzyme that intervenes in the last steps of estrogen production pathway. Triazoles are the core structures of nonsteroidal AIs. The nitrogen atom of the triazole moiety plays a fundamental role in the aromatase functionality by interacting with the iron ions of the heme group. In general, AIs possess numerous advantages as they quench the last step of estrogen synthesis without any inhibitory effects on the production of other steroids produced via the same pathway. Some AIs as anastrozole, letrozole, and vorozole have already been approved by the Food and Drug Administration in the treatment of breast cancer. The previously mentioned compounds present severe and adverse effects as polycystic ovary syndrome (PCOS), resistance onset on long-term treatments, and a higher risk of bone fractures. This review focuses intensively on the role of AIs in the treatment of hormone-sensitive types of cancers, especially the role of triazoles as nonsteroidal AIs. Also, the review provides an overview about the chemistry of triazoles along with the different methods by which the v-triazoles and s-triazoles are synthesized.
Chronic Hepatitis C is a global health threat and a silent killer. Regardless of the profound progress in preventing and treating this disease, research continues to discover new direct antiviral agents (DAAs), especially against novel targets. Our research has been directed to leverage the NS4A binding site to develop peptidomimetic inhibitors of the hepatitis C virus (HCV) NS3 protease. In previous reports, we could provide evidence of tunability of this site by peptide and nonpeptide NS3/4A inhibitors. In this report, we used structure-based techniques to design 1,2,3,4-tetrahydro-1,7-naphthyridine derivative as NS4A core mimics that cover the region between residues Ile-25′ to Arg-28′. The synthetic plan featured the Povarov reaction as an efficient strategy to construct the 1,7-naphthyridine core. Although this reaction has been reported in many literatures, critical assessments for its scope and limitations are scarce. In our work, we found that Povarov was extremely sensitive to alkene and aldehyde reactants. Moreover, using pyridine amines was not as successful as anilines. The most striking results were the lack of stability of compounds during purification and storage. The four compounds that survived the stability problems (1a-1d) did not show significant binding potency with NS3, because their structures were too simple to resemble the originally planned compounds.
The reductive cyclization of arenetellurols carrying α,β-unsaturated amide functionalities in the ortho position was investigated. Conceptually, such compounds can form 1,3-tellurazoles without the involvement of the unsaturation in the ring closure, they can form 1,4-tellurazinone derivatives, or they can undergo ring closure to 1,5-tellurazepinones. Amides derived from acrylic and methacrylic acid generated 1,5-tellurazepinones while 2-cinnamylamidobenzenetellurol cyclized to a 1,3-tellurazole derivative. In contrast, the reaction of acetylenedicarboxylic acid and its derivatives with 2-aminoarenetellurols generated 1,4-tellurazepinones, including a derivative of novel tricyclic naphtho [1, 4]tellurazinone. A comparison with analogous reactions of sulfur congeners indicates that their chemistry is a good predictor for the products obtained from 2-aminoarenetellurols. Selected compounds were characterized by X-ray crystallography. The present work offers access to previously unexplored organotellurium heterocycles.
Tandem conjugate addition–alkylation reaction of various amines with α-bromo-α, β-unsaturated ketones resulted in near-quantitative conversions into the corresponding aziridines when the reaction was carried out in the presence of 10 mol% of phase-transfer, PT catalysts in water. Some chiral quaternary ammonium salts derived from Cinchona alkaloids were investigated as water-stable PT catalysts. The scope and limitations of the reaction have also been investigated. The catalytic performances were significantly improved in comparison with the corresponding ordinary quaternary ammonium salt catalysts, and excellent yields (81%–96%) were obtained. Although an increase in the rate of aziridination has been accomplished, no stereoselectivity was observed. The positive values of the protocol have been confirmed.
The reaction of 4-benzoyl-5-phenylamino-2,3-dihydrothiophene-2,3-dione ( 1 ) with aminoheteroaryls, lamotrigine, 1,3-diaminoheteroaryls, dapsone, NH 2 R (hydroxylamine, DL -1-phenylethylamine, and metformin), and 4,4′-bipyridine in THF/H 2 O (1 : 1) at room temperature led to 3- N -phenylthiocarbamoyl-2-butenamides 2 – 5 , while that with naphthylamines and 1,3-phenylenediamine in ethanol at high temperature led to 5-phenylamino-2,5-dihydrothiophene-2-ones 6 – 8 as organic ligands in the medium to good yields. These showed the nucleophilic attacks of N -nucleophiles, except primary aromatic amines, on thioester carboxyl group (C-2) of thiophene-2,3-dione ring 1 . However, the nucleophilic attacks of primary aromatic amines on the carbonyl group (C-3) of thiophene-2,3-dione 1 occurred in the form of substituted thiophenes.
This study was performed to understand the site selectivity in the reaction between β-himachalene and meta-chloroperbenzoic acid (m-CPBA) in the first step followed by the addition of dibromocarbene (CBr2) to the main monoepoxidation product Pα formed in the first reaction. Calculations were performed using the Becke three-parameter hybrid exchange functional and the Lee–Yang–Parr correlation functional (B3LYP) with the 6-311 + G (d, p) basis set. Transition states were located by QST2, and their highlighting was validated by the existence of only one imaginary frequency in the Hessian matrix. The action of m-CPBA on β-himachalene was analyzed on the two double bonds of β-himachalene whose theoretical calculations show that the attack affects the most substituted double bond on α side containing hydrogen of ring junction. The obtained Pα product thereafter treated with dibromocarbene leads via an exothermic reaction to the six-membered ring double bond position of α-monoepoxide. The major products Pαα are kinetically and thermodynamically favored with a high stereoselectivity in perfect correlation with the experimental observations.
Some new fluorinated/nonfluorinated α -amino acids bearing 3-thioxo-5-oxo-1,2,4-triazin-6-yl and steroidal moieties have been obtained from condensation of the corresponding amino-triazinones with the steroid (Epiandrosterone). This was followed by the addition of HCN and, finally, acidic hydrolysis. The structure of the targets was established from their elemental analysis and spectral data. The amylolytic activity of the new products was evaluated against some fungi.
