Products 3a Research Articles

1,4-Naphthoquinone thiazoles: Synthesis, crystal structure, anti-proliferative activity, and inverse molecular docking study

In this study, 1,4-naphthoquinone thiazole hybrids were synthesized by reacting 1,4-naphthoquinone thioureas with various α-bromoketones in 78–86 % yields and characterized using 1H NMR, 13C NMR, FT-IR, and HRMS techniques. Furthermore, single crystal x-ray diffraction studies were also performed for 3b and 3c hybrids to determine stereochemistry. Density Functional Theory (DFT) calculations were performed to obtain additional information and to support the x-ray studies. The in vitro anti-proliferative activities of 1,4-naphthoquinone thiazoles were investigated against PC3 human prostate cancer cells. The products 3a–h showed anti-proliferative activity against PC3 cells, and the cell viability studies showed that the IC50 values of compounds 3f and 3e were 20.10 µM and 21.14 µM, respectively, while the other compounds exhibited lesser cytotoxic effects than the former two. Potential target underlying the mechanism of action of the synthesized compounds against prostate cancer was identified using inverse (reverse) docking method. Molecular dynamics simulation was also conducted to confirm the stability of the 3f/enzyme system. It was determined that the solubility in ethanol was better for compounds bearing methyl substituent on X1 location than compounds containing tert‑butyl on the same location. Compounds with F atom on X2 position were more soluble than the others in the corresponding groups.

Ultrasound-assisted Synthesis of Novel 4-[3-acetyl-2-(N-alkyl(aryl)acetamido)-1,3, 4-thiadiazol-5-yl]-3-(2-oxo-2H-chromen-3-yl)-1-(4-phenylthiazol-2-yl)-1H-pyrazoles: Anticancer Activities, Apoptotic, Cell Cycle, Molecular Docking, and ADMET Studies

Abstract: A novel series of 4-[3-acetyl-2-(N-alkyl(aryl)acetamido)-1,3,4-thiadiazol-5-yl]-3-(2-oxo-2Hchromen- 3-yl)-1-(4-phenylthiazol-2-yl)-1H-pyrazoles (2a-i) and 3 was synthesized in good yields. The methodology was depended on a one-pot four-components reaction of hydrazine hydrate, alkyl(aryl) isothiocyanate, 3-(2-oxo-2H-chromen-3-yl)-1-(4-phenylthiazol-2-yl)-1H-pyrazole-4-carboxaldehyde (1), and acetic anhydride in acetic acid under ultrasound irradiation. The spectral tools confirmed the structures of all synthesized compounds. Using the standard SRB method, the designed compounds were screened for their in vitro cytotoxicity properties against PC3, HepG2, and HCT116 human cancer cell lines. Products 2a and 2c worked best against all cancer cells tested, as well as doxorubicin. Apoptosis and cell cycle analyses were performed for the bioactive products 2a and 2c. Both products strongly impacted all tumor cells in the late apoptotic pathway and significantly inhibited all cancer cell types under investigation in both the S and G2 phases. After that, a molecular docking study was carried out on products 2a and 2c to investigate how they interact with the CDK-8 receptor. The ADMET prediction suggested that these bioactive products may be effective anticancer treatments.

Design, synthesis, characterization, structure-activity relationship, and molecular docking studies of novel 2,3-dihydropyrimidin-4(5H)-one and pyrimido[5,4–c] pyridazine-4-carbonitrile derivatives with biological evaluation

The key starting material, 2-imino-6-phenyl-2,3-dihydropyrimidin-4(5H)-one 1, was the focus of our approach due to the fact that it has an endocyclic active methylene group adjacent to the carbonyl function at position-5. We also further investigated the heterocyclization of the target products 3a–d with diverse carbon nucleophiles to generate fused pyrimidines. The authors provide a simple synthesis of heretofore unreported findings from two series of the novel 2,3,5,6-tetrahydropyrimido [5,4-c]pyridazine-4-carbonitriles 4a–d and 6a–c. The structures of the newly synthesized compounds have been confirmed via analytical and spectroscopic data. All compounds were screened against bacterial species (Escherichia coli, Bacillus megaterium, and Bacillus subtilis), and their antifungal activity was also tested against fungal species (Fusariumproliferatum, Trichodermaharzianum, and Aspergillus niger). Moreover, the minimum inhibitory concentration (MIC) was detected for all the studied compounds and revealed that all compounds had good to moderate results compared to the standby ones. Density function theory (DFT) at B3LYP via the 6–31 G (d,p) basis set has been calculated to explore the electronic properties of all studied compounds. Structure-activity relationship (SAR) was reported based on their electronic structure. Furthermore, molecular docking studies were conducted to evaluate the DFT results and visualize the activity of the compounds. The results displayed that those compounds (3b and 4a-d) were excellent scaffolds acting as antimicrobial agents.

Ultrasound-assisted synthesis of novel Schiff bases from 3-(2-oxo-2H-chromen-3-yl)-1-(4-phenylthiazol-2-yl)-1H-pyrazole-4-carboxaldehyde and their cytotoxicity, apoptosis, cell cycle, molecular docking, and ADMET profiling

With the ultimate goal of discovering new anticancer agents, this study involved the design and synthesis of fifteen novel Schiff bases 4a,b, 5, 6a–d, 7a–e, and 8–10 which contain 3-(2-oxo-2H-chromen-3-yl)-1-(4-phenylthiazol-2-yl)-1H-pyrazole moiety. The synthetic method depended on reaction of 3-(2-oxo-2H-chromen-3-yl)-1-(4-phenylthiazol-2-yl)-1H-pyrazole-4-carboxaldehyde (3) with a series of aromatic and heteroaryl amines under ultrasound irradiation to explore the influence of aromatic and heteroaryl rings on biological activity. The chemical structures of these Schiff bases were fully elucidated using various spectral and elemental analyses. The antiproliferative activities of the Schiff bases were studied by the standard SRB method. Among the new 15 Schiff bases, derivatives 4a,b, 5, and 7b have significant cytotoxic effects against PC3, HepG2, and HCT116 cancer cell lines. These four bioactive Schiff bases significantly increased the late apoptosis of all studied tumor cells. Also, both products 4a and 4b arrested the cell cycle at the G1 phase, while both compounds 5 and 7b arrested the S and G2 phases against PC3 cells. In addition, the products 4a, 4b, 5, and 7b have promising high abilities to arrest the cell cycle at the G2 phase against HepG2 and HCT116 cells. The different substitutions on the aryl ring were the basis for the structure–activity relationship study. The molecular docking study confirmed good binding interactions of these compounds with Cyclin-dependent kinase 8 (CDK-8) receptor, while the absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction supported that these bioactive products can be promising anticancer agents.

Multi-Component Syntheses of Spiro[furan-2,3'-indoline]-3-carboxylate Derivatives Using Ionic Liquid Catalysts.

Two previously described Brønsted acidic ionic liquids, 3,3'-(1,6-hexanediyl)bis(1-methyl)-1H-imidazolium hydrogen sulfate (Cat1) and 1,1'-(1,6-hexanediyl)bis(pyridinium) hydrogen sulfate (Cat2), were used as catalysts for the preparation of spiro[furan-2,3'-indoline]-3-carboxylate derivatives via a three-component reaction of anilines, isatins (N-alkyl-indoline-2,3-diones), and diethyl acetylenedicarboxylate, in high yields. The use of ultrasonic (US) irradiation led to the targeted products (1a-15a) in high yields ranging from 80% to 98%. Under the same conditions, the use of sulfuric acid and acetic acid as a Brønstedt catalyst did not yield the desired benchmark product 1a.

Two new cyclohexenone derivatives: Synthesis, DFT estimation, biological activities and molecular docking study

Two new cyclohexenone carboxylate derivatives (6a-b) were synthesized through an additional ring-forming chalcone. FT-IR, 1H, 13C NMR, and Mass spectroscopy techniques confirmed the skeletons. The antibacterial, antioxidant, and colon cancer HT-29 cell activity of synthetic substances were assessed. Compound 6a's IC50 is 23.95 and 60.28 for its antioxidant and anticancer activities, whereas Compound 6b's IC50 is 27.56 and 62.72, respectively. MIC values for compound 6a are 15.75 ± 1.12, 10.25 ± 1.27, and 65.61 ± 1.72 against Staphylococcus aureus, Escherichia coli bacterial strains, and Candida albicans, respectively, whereas for compound 6b is equal to 18.32 ± 1.53, 12.63 ± 1.36, and 78.91 ± 1.94. Based on the extent of (B3LYP) and a 6-31G (d, p) basis set, the HOMO and LUMO of synthesized compounds were computed using the density functional theory (DFT) method. Energy gaps for products 6a and 6b are 2.8272 and 2.3360, respectively. Docked products had binding affinities of −9.5 and −9.1 for compounds 6a and 6b, respectively, with the crystal structure of recombinant human acetylcholinesterase in complex with donepezil (PDB ID: 4ey7). Consequently, according to experimental and computational studies, compound 6a is more active than compound 6b.

Pd-catalyzed synthesis, characterization, and biological evaluations of pyrazole derivatives: DFT, molecular modelling and antioxidant studies

Using Pd(PPh3)4 as a catalyst, a new series of coupling products (5a–5l) synthesized from pyrazole derivatives (4a-4c) and substituted boronic acids. Afterward, 1H, 13C-NMR, FT-IR, UV-visible, and LC-MS techniques were used to characterize the pyrazole derivatives. These pyrazole derivatives (4a-4c and 5a-5l) were assessed for their in-vitro antifungal activity, growth pattern evaluations, and hemolytic assays against the Candida strains. The antibacterial inhibitory potential of the lead compound 5c, with a panel of three Gram-positive bacterial strains and two Gram-negative bacterial strains, was employed to find out MIC, FICI, and toxicity. Results showed that the MIC values with all bacterial strains for compound 5c indicate substantial antimicrobial potential. Analog 5c was tested for its ability to interact with Ct-DNA using various techniques. Compound 5c showed binding constants (Kb) of 9.93 × 105 M−1 while the Gibbs free energy was -34.22 kJmol−1. The linear Stern-Volmer constant (KSV) for 5c was calculated to be 4.81 × 104. DFT calculation study has been investigated for the geometrical optimization and energy parameters calculation. Pyrazole derivative 5c was used for molecular modelling investigation with PDB: 1BNA, 2XCT, and 5FSA, which validated the manner of binding and supported in vitro DNA binding results. Utilizing the DPPH and H2O2 assay, derivative 5c was also tested for antioxidant activity.

Magnetically separable new Fe3O4@AgZr2(PO4)3 nanocomposite catalyst for the synthesis of novel isoxazole/isoxazoline-linked 1,2,3-triazoles in water under ultrasound cavitation

In this work, we report a novel magnetically separable Fe3O4@AgZr2(PO4)3 as heterogeneous nano-composite catalyst for the one-pot four-step cascade sulfonylation/Huisgen 1,3-dipolar cycloaddition/azidation/click reactions in water under ultrasound cavitation. This strategy appears to be suitable for obtaining new analogues of isoxazole/isoxazoline-linked 1,4-disubstituted 1,2,3-triazoles in sustainable way starting from propargyl or allyl alcohol/sulfonyl chloride/oximes/sodium azide/and terminal alkynes. The effects of ultrasonic probe position as well as vessel shape on the chemical reaction were investigated. Three different types of 25 mL glass vessels were used in this study: round-bottomed flasks, erlenmeyer flasks and pear-shaped flasks. The heterogeneous nanocomposite was synthesized by supporting magnetic Fe3O4 nanoparticles on AgZr2(PO4)3 material (Fe3O4@AgZr2(PO4)3). The crystalline nature and purity of the catalyst were characterized using various techniques, including FT-IR, EDX, and XRD. Dispersity and morphology were characterized by SEM analysis. The findings indicate that Fe3O4 particles ranging in size from 50 to 75 nm were evenly distributed on the surface of AgZr2(PO4)3. The use of an aqueous reaction medium, the simple and inexpensive recovery of the catalyst by the application of an external magnet and the high and constant catalytic efficiency over at least five consecutive cycles make this protocol more interesting from an operational point of view. All synthesized products 6a–j and 7a–f were prepared in excellent yields (86–95 %) in short reaction time (2.25h). Their structures were confirmed by FT-IR, 1H NMR, 13C NMR, ESI-MS and HPLC analyses.

Synthesis, Characterization and Calculations of Linear and Nonlinear Optical Properties of Acrylonitrile Substituted Spirocyclotriphosphazene Derivatives

There methoxy-substituted acrylonitrile compounds (2a, 2b and 2c) were synthesized using method described in the literature. Compounds 3a, 3b and 3c were obtained by using the microwave demethylation method for the first time, then they were reacted with 2,2-dichloro-4,4,6,6-bis[spiro(2′,2″-dioxy-1′,1″-biphenylyl)]-cyclotriphosphazene (DPP) to reach final products 4a, 4b and 4c. The structures of the substituted compounds were determined by elemental analysis, MALDI-TOF, 1H, [Formula: see text]C APT, [Formula: see text]P NMR and FT-IR spectroscopy. In order to investigate the usability potential of the synthesized products 4a, 4b and 4c in optoelectronic devices, we experimentally measured the band gaps and calculated their nonlinear optical properties by Density Functional Theory (DFT) method. Obtained results showed that the introduction of an electronegative substituent (F) or an electropositive substituent (CH[Formula: see text] to the parent compound 4a has minimal impact on the absorption spectra. However, the fluorine-substituted compound 4b exhibits considerably higher values in terms of dipole moment, averaged polarizability, and first-hyper polarizability when compared to compounds 4a and 4c. Calculated values of dipole moment, averaged polarizability, first-hyper polarizability, electronegativity and global hardness of the fluorine-substituted compound 4b were found to be 6.281 (debye), −393.592 (1.4818 × 10[Formula: see text] cm[Formula: see text], 899.857 (8.641 × 10[Formula: see text] cm5/e.s.u), 4.492 (eV) and 1.922 (eV), respectively. These values were the highest in magnitude in comparison to the associated values of 4a and 4c. Overall results indicated that the influence of introducing an electropositive substituent (CH[Formula: see text] to the parent compound 4a, resulting in decreased stability and increased reactivity. Conversely, the introduction of an electronegative substituent (F) to 4a leads to opposite effects.

Ce-ZSM-5: A highly capable catalyst for the construction of acridines in water and their computational study against DNA gyrase protein.

Cerium doped ZSM-5 (Ce-ZSM-5) as an environmentally benign and reusable catalyst for the construction of acridines in aqueous medium. This method produced corresponding acridines with good yields and shorter reaction times. Also avoids the use of hazardous solvents and involves a simple work-up process. The solid catalyst was prepared by doping Ce ions with ZSM-5 (Zeolite Socony Mobil-5) and confirmed by XRD, BET SA-PSD and SEM. The synthesised acridine derivatives were confirmed by 1H NMR, 13C NMR and FTIR spectroscopic data. The docking studies of the synthesised compounds are performed by the PyRx auto dock tool against DNA gyrase protein. The products 5a and 6d are found to be the best fit ligands against DNA gyrase protein.

Novel oxidation system of benzoins to benzils for synthesis and antioxidant activity studies of (5-oxo-4,4-diarylimidazolidin-2-ylidene)cyanamides

In this work, the two novel methods were achieved for the preparation of benzil derivatives 2a–f with high yields and short reaction time from benzoins 1a–f via; (i) their refluxing with a mixture of sulfur and morpholine in ethanol, and (ii) their stirring with oxidizing agent “DMSO-NaBr-H2SO4 system” at 85 °C. Thus, a new series of (5-oxo-4,4-diarylimidazolidin-2-ylidene)cyanamide 3a–f was already synthesized from the reaction of benzils 2a–f with commercially available cyanoguanidine in the presence of sodium ethoxide as a basic catalyst. The new products 3a–f were exhibited promising antioxidant activity based on “in vitro” assays in 2,2-diphenyl-1-picrylhydrazyl (DPPH) compared to vitamin C.

Metal free synthesis of substituted 5-aryl/alkyl aminotetrazoles in water

The synthesis of tetrazoles is established under metal free conditions at room temperature in the presence of open air. The reaction of 2-bromoaryl isothiocyantes with amines gives thiourea that undergoes reaction in situ with NaN3 using Iodine in the presence of water medium to afford 1-(2-bromophenyl)-N-5-arylaminotetrazoles via substitution followed by electrocyclization processes at ambient temperature. All electron donating and withdrawing substituents readily underwent the reaction to get the corresponding final products 2a–2ab in moderate to good yield. This methodology has also applied for gram-scale quantity of tetrazoles. In addition, our aqueous micellar medium has shown good recyclability activity and it has exhibited good yield of the product up to four cycles.

Enzymatic biosynthesis of novel 2-(2-phenylethyl)chromone glycosides catalyzed by UDP-glycosyltransferase UGT71BD1

2-(2-Phenylethyl)chromones (PECs) are the main bioactive components of agarwood which showed diverse pharmaceutical activities. Glycosylation is a useful structural modification method to improve compounds’ druggability. However, PEC glycosides were rarely reported in nature which largely limited their further medicinal investigations and applications. In this study, the enzymatic glycosylation of four naturally separated PECs 1−4 was achieved using a promiscuous glycosyltransferase UGT71BD1 identified from Cistanche tubulosa. It could accept UDP-Glucose, UDP-N-acetylglucosamine and UDP-xylose as sugar donors and conduct the corresponding O-glycosylation of 1−4 with high conversion efficiencies. Three O-glucosylated products 1a (5-hydroxy-2-(2-phenylethyl)chromone 8-O-β-D-glucopyranoside), 2a (8-chloro-2-(2-phenylethyl)chromone 6-O-β-D-glucopyranoside) and 3a (2-(2-phenylethyl)chromone 6-O-β-D-glucopyranoside) were prepared and structurally elucidated as novel PEC glucosides based on NMR spectroscopic analyses. Subsequent pharmaceutical evaluation found that 1a showed remarkably improved cytotoxicity against HL-60 cells, whose cell inhibition rate was 19 times higher than that of its aglycon 1. The IC50 value of 1a was further determined to be 13.96 ± 1.10 μM, implying its potential as a promising antitumor-leading candidate. To improve the production of 1, docking, simulation and site-directed mutagenesis were performed. The important role of P15 in the glucosylation of PECs was discovered. Besides, a mutant K288A with a two-fold increased yield for 1a production was also afforded. This research reported the enzymatic glycosylation of PECs for the first time, and also provide an eco-friendly pathway for the alternative production of PEC glycosides for leading compounds discovery.

Visible-light promoted catalyst-free (VLCF) multi-component synthesis of spiro indolo-quinazolinone-pyrrolo[3,4-a]pyrrolizine hybrids: evaluation of in vitro anticancer activity, molecular docking, MD simulation and DFT studies

A new and highly efficient visible-light-promoted catalyst free (VLCF) strategy for neat and clean synthesis of spiro indolo-quinazolinone-pyrrolo[3,4-a]pyrrolizine hybrids (6a–d) has been introduced. We have performed visible-light triggered 1,3-Dipolar cycloaddition reaction of maleimide (5a–d) with azomethine ylide generated in situ derived from tryptanthrin (3) and L-proline (4) to obtain desired products (6a–d) in good to excellent yield. Authentication and characterization of product was done using various spectroscopic techniques such as IR, 1H NMR, 13C NMR, Mass spectrometry and single crystal XRD analysis. To explain the reaction spontaneity, product stability, reactivity as well as possible mode of the interaction a quantum chemical investigation was performed and depicted through DFT studies. The synthesized compound 6a was also evaluated for anti-proliferative activity against a panel of five cancer cell lines (MCF-7, MDA-MB-231, HeLa, PC-3 and Ishikawa) and normal human embryonic kidney (HEK-293) cell line by using MTT assay. Compound 6a showed very good in vitro anti-proliferative activity (IC50 = 6.58–17.98 μM) against four cancer cell lines and no cytotoxicity against normal HEK-293. In order to evaluate the anticancer potential of compounds 6a-d, molecular docking was performed against wild type and mutant EGFR. The results suggest that all the compounds occupied the active site of both enzymes, with a strong binding energy (−10.2 to −11.5 kcal/mol). These results have been confirmed by molecular dynamics simulation by evaluating root mean square deviation (RMSD) and root mean square fluctuation (RMSF), along with principal component analysis (PCA). Communicated by Ramaswamy H. Sarma

Design, synthesis and antitumor activity of coumarin, isoxazole, pyrazole, pyridine and pyrimidine compounds: 3β-hydroxypregn-5-ene-20-one derivatives

In continuation of our reserach for synthesizing heterocyclic derivatives with a broad range of biological activities, the current research was performed to synthesize 3β-hydroxypregn-5-ene-20-one derivatives of coumarin, isoxazole, pyrazole, pyridine and pyrimidine and screen for antitumor activity. Synthesis of amino-thiopephen derivatives (1a-1b) was performed through reaction of 3β-hydroxypregn-5-ene-20-one with ethyl cyanoacetate or malononitrile and sulphur. 3β-Hydroxypregn-5-ene-20-one was reacted with ethyl cyanoacetate in the presence of hydrazine, urea or thiourea to obtain aminopyrazole (3), aminopyrimidine (4a-4b) derivatives, respectively. The amino-thiophene derivatives (1a-1b) further reacted with either phenylisothiocyanate or benzoylisothiocyanate to form fused thienopyrimidine derivatives (5a-5d). The products 1a and 1b were also treated with ethyl cyanoacetate to afford cyanoacetamidothiophene derivatives (6a-6b) which were converted to fused thienopyridone derivatives (7a-7b) through cyclization reaction. The compounds 6a and 6b were allowed to react with different carbonyl compounds including salicyaldehyde, cyclopentanone-sulphur mixture, acetylacetone and malonaldehyde to prepare coumarin (8a-8b), cyclopentylthiophene (9a-9b) and 2-pyridinone (10a-10d) derivatives respectively. Furthermore, the reactions of hydroxylamine hydrochloride and benzoylacetonitrile with the compounds 6a-6b separately afforded new aminoisoxazole (12a-12b) and phenylpyridone (14a-14b) derivatives, respectively. The structures of new products were established through IR, 1H NMR, 13C NMR spectroscopic and mass spectrometric analysis. The synthesized compounds (1a-1b to 14a-14b) displayed in-vitro antitumor activity against human cell-lines, including MCF-7 (breast adenocarcinoma), SF-268 (CNS cancer) and NCI-H460 (non-small lung cancer cell). The results suggested that all the screened products exhibited cell growth inhibitory activity in a dose-dependents manner. However, the compound 12a showed highest level of inhibition against all three cell-lines.

Synthesis and X-ray crystallography of new N-, O-acyl pseudoephedrines

N-acylation and O-acylation of pseudoephedrine are studied by using aroyl chlorides and/or ethyl chloroformate as acylating agents. Thus, treatment of pseudoephedrine or its salt with benzoyl or p-nitrobenzoyl chlorides affords the corresponding N- or O-acylated products 2a, b, 3a, b and 4. Also, pseudoephedrine 1 was allowed to react with ethoxymethylenemalononitrile to yield 2-hydroxy-1-methyl-2-phenylethyl](methyl)amino}methylene)malononitrile (5). New oxazolidine derivatives 6a–c were conveniently synthesized in high yields from the reaction of 1 with different bis(methylthio)yledinenitriles. X-ray crystallographic study of 4 revealed that the compound crystallized in orthorhombic system. The structure is stabilized by the intermolecular interactions as well as a network of hydrogen bond contacts, conformed parallel layers.

Chitosan catalyzed synthesis and mechanistic study of steroidal 2H-pyran ring formation

A simple and convenient method is reported for the preparation of steroidal 2H-pyran 2 by reacting 3β-acetoxy cholest-5-ene-7-one 1 with N-benzyl-2-cyanoacetamide in presence of chitosan, a green and heterogeneous catalyst. The product 2 was characterized by using NMR (1H and 3C), IR, and mass spectroscopy. The mechanism of 2H-pyran ring formation is described by employing theoretical B3LYP/6-31G (d) density functional method. The reaction undergoes via formation of two intermediates A and B, and each intermediate undergoes through a transition state TS1 and TS2. The molecular properties like relative energy and FMO analysis were used to explain the mechanism of the reaction. The HOMOs and LUMOs were found in support of the present reaction mechanism. The stability of all the calculated structures which includes reactant (1a), intermediates (A and B), product (2a) as well as TS1 and TS2 transition states, was supported by calculating their energy minima and fundamental frequencies.

Spectroscopic, X-ray, mechanistic and DFT studies on formation of novel benzoimidazole-4-ones from cyclohexenyl carbothioamides

Spectroscopic studies of cyclohexenyl carbothioamides 2, obtained from condensation of 1,3-cyclohexandione with aryl isothiocyanates, predicted the proton transfer behaviour in solid, solution and gaseous phases. DFT studies in gaseous and solution phase shows good congruence with the experimental findings. Condensation of cyclohexenyl carbothioamide 2a with hydrazine hydrate unexpectedly embellished novel 2-(4-chlorophenyl)amino)-2,5,6,7-tetrahydro-4H-benzo[d]imidazol-4-one 4a and 2-(bis((4-chlorophenyl)amino)methylene)cyclohexane-1,3-dione 3a instead of the presumable 2H and 1H-indazole derivatives 5a and 6a, respectively. The proposed mechanism of formation of unconventional products 3a and 4a supported by experimental results is described. Spectroscopic investigations such as FT-IR, Mass and NMR (1H, 13C, DEPT-135, HSQC, COSY, NOESY) along with X-ray crystallographic results established the structure of two derived novel products 3a and 4a. The interesting feature of this study is NN bond cleavage of strained transit diazetidine ring and formation of CN bond leading to generation of novel benzoimidazol-4-one derivative 4a. Hirshfeld surface analysis of entitled compounds is reported.

An efficient synthesis of new 3,5‐bis(2‐arylthiazol‐4‐yl)‐1,2,4‐oxadiazole derivatives and their antimicrobial evaluation

AbstractA new series of 3,5‐bis(2‐arylthiazol‐4‐yl)‐1,2,4‐oxadiazole (8a–o) has been synthesized by modified reaction conditions. The reaction of ester 7a with N′‐hydroxy‐2‐phenylthiazole‐4‐carboximidamide 6a using NaOH in DMSO gave the formation of product 8a up to 40% yield. In the second method, the reaction with K2CO3 in toluene at reflux conditions gave a 50% yield. In the third method, the reaction condition was modified. The ester 7a was hydrolyzed to acid 9a. The reactions of acid 9a using N,N‐dimethyl amino pyridine (DMAP) in N,N‐dimethylformamide (DMF), followed by the addition of N‐(3‐dimethylaminopropyl)‐N′‐ethylcarbodiimide hydrochloride (EDC·HCl), and then N′‐hydroxy‐2‐phenylthiazole‐4‐carboximidamide 6a, furnished a 65% yield of 8a. The compounds 8b–o were synthesized using DMAP and EDC·HCl as coupling reagents and gave 60%–72% yields. The structure of newly synthesized compounds was confirmed by spectral analysis. The synthesized compounds were screened for in vitro antimicrobial activity against Escherichia coli (NCIM 2574), Proteus mirabilis (NCIM 2388), Bacillus subtilis (NCIM2063), Staphylococcus albus (NCIM 2178), Candida albicans (NCIM 3100), and Aspergillus niger (ATCC 504). Among the 8a–o derivatives, eight compounds 8c, 8e, 8f, 8g, 8i, 8j, 8k, and 8l showed good activity S. albus with a MIC 31.25–62.5 μg/mL.

Synthesis, Molecular Docking, and Cytotoxic Evaluation of Fluorinated Podophyllotoxin Derivatives

Objective: The study was conducted to evaluate the in vitro and in silico anticancer activity of fluorinated podophyllotoxin derivatives. Methods: Microwave-assisted multicomponent reactions were carried out in an Anton Paar Microwave Synthetic Reactor Monowave 400 in order to synthesize fluorinated podophyllotoxin derivatives. These products were identified by spectral analysis and evaluated for their cytotoxicity against 4 types of human cancer cell lines (KB, HepG2, A549, and MCF7), as well as human embryonic kidney (Hek) 293 cells using MTT protocol. Molecular docking was conducted using 2 crystal structures of tubulin—colchicine (PDB ID: 4O2B) and topoisomerase II—etoposide (PDB ID: 3QX3) complexes. Results: Two potent cytotoxic fluorinated podophyllotoxin–naphthoquinone compounds were synthesized in good yields. They displayed high cytotoxic activity against all the tested cell lines, with IC50 values ranging from 0.58 to 3.17 µM. Notably, product 8a showed low toxicity against the Hek-293 cell line. Molecular docking results showed that products 8a and 8b participated in the same key interactions provided by etoposide with both topoisomerase and DNA chain domains. The binding energy values calculated for 8a and 8b are acceptable. Conclusion: This study revealed that products 8a and 8b exhibited promising in vitro and in silico anticancer activity and could be recognized as promising anticancer agents.