Synthesis of novel triazoloquinoxaline-pyrazole hybrids as antiproliferatives,EGFR inhibitors,and apoptosis inducers

Novel triazoloquinoxaline-pyrazole hybrids have been developed and synthesized. All derivatives' anticancer activity has been evaluated using Sulforhodamine-B (SRB) assay for cancer cell lines MCF-7, HepG-2, and HCT-116. Compound 12b was 2-fold more cytotoxic than Doxorubicin, while 12a , c demonstrated comparable cytotoxicity to the reference Doxorubicin. Further investigations on the most active derivatives 12a-c were done to study their inhibitory activity on two EGFR subtypes wild EGFR and mutant EGFR (L858R) tyrosine kinases in MCF-7 cell lines. Compound 12b exhibited potent inhibitory activity toward wild EGFR (IC₅₀: 0.98 μM) when compared to Gefitinib (IC₅₀:18.07 μM). 12b also possessed a marked inhibition against mutant EGFR (L858R-TK) exhibiting (IC₅₀:27.45 μM) in comparison to Lapatinib (IC₅₀: 61.06 μM). Compound 12b improved the active Caspase-3 value and the BAX/Bcl-2 reference. Furthermore, 12b showed G2/M cell cycle arrest induced apoptosis in cell line MCF-7. In addition, the most active derivatives have been orally bioavailable as shown in the in silico determination of the ADME characters. The binding pattern of compound 12b was also studied by molecular docking.     

Novel Pyridothienopyrimidine Derivatives: Design,Synthesis and Biological Evaluation as Antimicrobial and Anticancer Agents

The growing risk of antimicrobial resistance besides the continuous increase in the number of cancer patients represents a great threat to global health, which requires intensified efforts to discover new bioactive compounds to use as antimicrobial and anticancer agents. Thus, a new set of pyridothienopyrimidine derivatives 2a,b–9a,b was synthesized via cyclization reactions of 3-amino-thieno[2,3-b]pyridine-2-carboxamides 1a,b with different reagents. All new compounds were evaluated against five bacterial and five fungal strains. Many of the target compounds showed significant antimicrobial activity. In addition, the new derivatives were further subjected to cytotoxicity evaluation against HepG-2 and MCF-7 cancer cell lines. The most potent cytotoxic candidates (3a, 4a, 5a, 6b, 8b and 9b) were examined as EGFR kinase inhibitors. Molecular docking study was also performed to explore the binding modes of these derivatives at the active site of EGFR-PK. Compounds 3a, 5a and 9b displayed broad spectrum antimicrobial activity with MIC ranges of 4–16 µg/mL and potent cytotoxic activity with IC₅₀ ranges of 1.17–2.79 µM. In addition, they provided suppressing activity against EGFR with IC₅₀ ranges of 7.27–17.29 nM, higher than that of erlotinib, IC₅₀ = 27.01 nM.     

Synthesis of novel tetra-substituted benzimidazole compounds containing certain heterostructures with antioxidant and anti-urease activities

A new series of 5,6-dimethyl-2-phenyl-1H-benzimidazole derivatives was synthesized. The antioxidant activities of the synthesized compounds were determined according to the cupric reducing antioxidant capacity (CUPRAC), ABTS, and DPPH assays. Many of the target compounds showed good antioxidant activity. Among these compounds, it has been determined that the carbothioamide and 1,2,4-triazole derivatives had a very good antioxidant capacity. Also, all compounds were screened for in vitro inhibitory activity against Jack bean urease. Among the synthesized molecules, the starting compound, acetate, and acetohydrazide derivatives (with IC₅₀ values 12.02, 11.40, and 8.04 μg/mL, respectively) had a higher inhibitory effect on urease and exhibited a lower IC₅₀ values than acetohydroxamic acid (IC₅₀: 20.50 μg/mL) and thiourea (IC₅₀: 14.04 μg/mL) as a reference inhibitors.     

Indeno[1,2-b]pyridin-5-one derivatives containing azo groups and their hydrazonal precursors: Synthesis,antimicrobial profile,DNA gyrase binding affinity,and molecular docking

The prevalence of germs that are resistant to many antibiotics is rising rapidly the world over. There is a large group of researchers actively looking for better medicines. Here, we designed two series of hydrazonal and indeno[1,2-b]pyridin-5-one bearing hydrazone and azo-groups to test their antimicrobial activity. Molecular structures of all derivatives were assured based on their spectral data and elemental analyses. Results of the antimicrobial activity of the tested hydrazone and azo compounds showed promising potential for several derivatives. The minimum inhibitory concentrations (MICs) of hydrazones 4a - h and 6a - g displayed good antibacterial reactivities with a range of 3.91–250 μg/mL and moderate antifungal activity with a range of 15.6–500 μg/mL. The most promising hydrazone 4f and azo- 6a compounds demonstrated MIC values against Streptococcus faecalis and Escherichia coli equal to 3.91 and 7.81 μg/mL, respectively. Moreover, azo compound 6a showed MIC value equal to 3.91 μg/mL against Enterobacter cloacae species. Additionally, derivative 4f exhibited a significant inhibitory profile against the E. coli gyrase A enzyme (IC₅₀ = 5.53 μg/mL). On the other hand, compound 6a (IC₅₀ 14.05 μg/mL) exhibited the lowest DNA gyrase inhibitory activity as compared to compounds 4f and reference standard drug novobiocin, IC₅₀ 5.53 and 1.88 μg/mL, respectively. Pharmacokinetic and pharmacodynamic profiles and molecular docking studies for the two most promising molecules 4f and 6a were computed and revealed that both compounds have good ADME profiles and high binding affinity to DNA gyrase binding site.     

Ammonium metavanadate as an efficient catalyst for the synthesis of 2,4,5‐triaryl‐1H‐imidazoles

Ammonium metavanadate (NH₄VO₃) is an inexpensive, efficient and mild catalyst for the synthesis of 2,4,5‐triaryl‐1H‐imidazole from the one‐pot three‐component condensation of benzil/benzoin, an aldehyde and ammonium acetate in excellent yield. This method has the advantages of good yield, green catalyst, simple procedure, much faster reactions. J. Heterocyclic Chem., (2011).     

Synthesis and antitumor evaluation of some new derivatives and fused heterocyclic compounds derived from thieno[2,3-b]pyridine: Part 2

As a continuation of our research on developing anticancer agents and based on the proven proprieties of thieno[2,3-b]pyridines as anticancer, we have designed to synthesize novel thieno[2,3-b]pyridine derivatives that incorporate different biologically active heterocycles through various chemical reactions. All of the newly obtained compounds, compared with the standard anticancer drug (doxorubicin), were screened in vitro for their antitumor activity against hepatocellular carcinoma (HepG-2) and human breast cancer (MCF-7) cell lines. The results revealed that compounds 3 , 7 , 12 , and 19 were found to be the most potent against both HepG-2 and MCF-7 cell lines exhibiting IC₅₀ values ranging from 3.67 to 11.50 and 5.13 to 11.80 μg/mL, respectively, among which compound 7 has a more potent activity than the reference drug doxorubicin against HepG-2 cell line, showing IC₅₀ value of 3.67 μg/mL (doxorubicin 4.65 μg/mL).     

Synthesis and Reactions of Some New Heterocyclic Compounds Containing Cycloalka[e]thieno[2,3‐b]pyridine Moiety

Hydrolysis of ethyl 3-amino-4-aryl-cycloalka[e]thieno[2,3-b]pyridine-2-carboxylates ( 3a-d) gave the corresponding o-aminocarboxylic acids 4a-d . Heating the latter compounds ( 4a-d) with acetic anhydride furnished the oxazinone derivatives 5a-d which, in turn, underwent recyclization reaction to give the corresponding pyrimidinones 6a-d upon treatment with ammonium acetate in acetic acid. Reaction of 3-amino-4-aryl-cycloalka[e]thieno[2,3-b]pyridine-2-carboxamides ( 3f,h ) with triethyl orthoformate gave pyrimidinone derivatives 7a,b . Reaction of 3-amino-4-phenyl-cycloalka[e]thieno[2,3-b]pyridine-2-carboxamides 3e,h with aromatic aldehydes furnished tetrahydropyridothienopyrimidinones 8a-d . Chlorination of 7a,b and 6a-d by using phosphorous oxychloride produced 4-chlorocycloalka[5′,6′]pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine derivatives 9a-f which were used as key intermediates in the synthesis of several new cycloalkapyrido-thienopyrimidines 10a-f ˜ 14a-f . Moreover, some cycloalkapyridothienotriazinones 15a,b-17a,b were synthesized.     

Synthesis of diverse (E)-2-((1H-imidazol-1-yl)methyl)-2-((benzyloxy)methyl)-2,3-dihydro-1H-inden-1-one O-benzyl oxime derivatives as potent antileishmanial agents

A series of (E)-2-((1H-imidazol-1-yl)methyl)-2-((benzyloxy)methyl)-2,3-dihydro-1H-inden-1-one O-benzyl oximes ( 6a-j ) were prepared and evaluated for their in vitro antileishmanial potency against Leishmania donovani (in promastigote and amastigote models). At a concentration of 05-μg/mL, compounds 3a-d , 4a-d , 5a , 5b , 6a-d, and 7a-d exhibited 97% to 100% and 87% to 100% inhibition against promastigotes and amastigotes, respectively. Compounds 6a , 6d-6j and 6a , 6i , 6j exhibited equal antileishmanial potency to that of SSG and Pentamidin at lower values of IC₅₀.     

Chemical composition and biological activities of essential oil from Filifolium sibiricum (L.) Kitam

The essential oil from Filifolium sibiricum (L.) Kitam were extracted using hydrodistillation and GC-MS was used to analyse the essential oil. The main components were espatulenol (8.55%), geranyl acetate (8.03%), caryophyllene oxide (5.47%), calamenene (4.79%), geraniol (4.28%), calamenene (4.53%), geraniol (4.06%), cedrene epoxide (3.23%), myrtenol (3.18%), transgeranylgeranio (3.13%), etc. The essential oil showed intensive inhibitory effects against MCF-7 with IC₅₀ level of 0.78 mg/mL, HepG-2 with IC₅₀ level of 0.44 mg/mL, SKOV-3 with IC₅₀ level of 0.27 mg/mL, BGC-823 with IC₅₀ level of 0.34 mg/mL. In the antibacterial test, the essential oil showed the significant antibacterial activities. The MIC and MBC values were 5.20 and 5.20 mg/mL against Staphylococcus aureus.     

Bioassay‐guided isolation of an active compound with protein tyrosine phosphatase 1B inhibitory activity from Sargassum fusiforme by high‐speed counter‐current chromatography

A rapid and efficient method using high‐speed counter‐current chromatography was established for the bioassay‐guided separation of an active compound with protein tyrosine phosphatase 1B inhibitory activity from Sargassum fusiforme. Under the bioassay guidance, the ethyl acetate extract with the best IC₅₀ value of 0.37 ± 0.07 μg/mL exhibited a potential protein tyrosine phosphatase 1B inhibitory activity, which was further separated by high‐speed counter‐current chromatography. The separation was performed with a two‐phase solvent system composed of n‐hexane/methanol/water (5:4:1, v/v). As a result, dibutyl phthalate (19.7 mg) with the purity of 95.3% was obtained from 200 mg of the ethyl acetate extract. Its IC₅₀ was 14.05 ± 0.06 μM, which was further explained by molecular docking. The result of molecular docking showed that dibutyl phthalate enfolded in the catalytic site of protein tyrosine phosphatase 1B. The main force between dibutyl phthalate and protein tyrosine phosphatase 1B was the hydrogen bond interaction with Gln266. In addition, hydrogen bond, van der Waals force and hydrophobic interaction with the amino acids (Ala217, Ile219, and Gly220) were also responsible for the stable protein‐ligand complex.     

Synthesis of new imidazo[4,5-d][1,3]diazepine derivatives from 5-amino-4-(cyanoformimidoyl)imidazoles

N¹-[(Z) -2- Amino-1,2-dicyanovinyl]formamidines 1a-d react readily with tosyl isocyanate to form novel 8-amino-3-substituted-5-oxo-7-tosylaminoimidazo[4,5-d][1,3]diazepines 6a-d rather than the 6-cyano-2-oxopurine derivatives 5a-d expected. Compound 5a has been synthesized from 1a by reaction with ethyl chloroformate and base-catalyzed cyclization of the resultant 5-ethoxycarbonylamino-4-(cyanoformimidoyl)imidazole. Treatment of the 5-amino-4-cyanoimidazoles 7a and b with tosyl isocyanate under similar conditions gives the 4-cyano-5-(3′-tosylureido)imidazoles 8a and b , which on treatment with ethanolic ammonia cyclizes to the corresponding isoguanines 10a and b .     

Antioxidant and DNA damage protecting activities of newly synthesized thiol bridged bis-benzimidazole derivative and its dicationic analogue

Two new types of bis-benzimidazole derivatives containing thiol group have been prepared and characterized. The compounds contain sulfur with imidazole ring show promising biological activities such as antioxidant, anticancer, antimicrobial and etc. The aim of this study was synthesis of benzimidazole derivatives which not only show antioxidant activity but also protect DNA from oxidative damage. Antioxidant activities of the synthesized compounds were investigated with DPPH and hydrogen peroxide radical scavenging assays. DNA nicking assay was applied to establish activity of compounds to protect plasmid DNA from Fenton's reagent radicals. Both compounds had antioxidant activity, however, activity of dicationic analogue was greater than well-known antioxidant Vit C. IC₅₀ values calculated according to DPPH method were 14.5 μM for dicationic analogue ( 2 ) and 57.5 μM for 1,2-bis(1-methyl-1H-benzo[d]imidazol-2-ylthio)ethane ( 1 ). In hydrogen peroxide scavenge assay IC₅₀ values of compounds were 638.6 μg/mL for 1,2-bis(1-methyl-1H-benzo[d]imidazol-2-ylthio)ethane ( 1 ), 398.9 μg/mL for dicationic analogue ( 2 ). Furthermore, dicationic analogue promised an effective DNA protection due to its positive charge interacting with negatively charged DNA. Also the high solubility of the dicationic analogue in water due to its positive charge could provide a great advantage in biological applications.     

Synthesis and antimicrobial activity of some new coumarin and dicoumarol derivatives

PTC reaction of coumarin derivative 1 with alkyl halides afforded C₄ oxygen alkylation products 2a-d in appreciative yield, whereas with phenyl isothiocyanate gives the C₃ addition product 4 ; also, one-pot three-component PTC reaction was investigated. Treatment of coumarin 1 with aromatic aldehydes in different molar ratios gives 3-arylidene derivatives 7a,b and the dicoumarol derivatives 8a,b . Pyrano chromene 9 and pyrano pyridine 10 were obtained by reaction of arylidene 7a with ethyl acetoacetate through Michael cycloaddition reaction. The stability of pyrone ring in 3-arylidene 7 and dicoumarol 8 towards different nucleophilic reagents under reflux and/or fusion conditions has been studied by the action of hydrazine hydrate, ammonium acetate, methyl amine, and p-toluidine afforded compounds 11 and 13a-c . The antimicrobial activity of some synthesized compounds has been investigated.     

An ancient remedial repurposing: synthesis of new pinocembrin fatty acid acyl derivatives as potential antimicrobial/anti-inflammatory agents

Five new pinocembrin derivatives (MC1-MC5) were synthesized by Steglich reaction, and investigated for their antimicrobial, antioxidant, and anti-inflammatory activity. MC2 (oleoyl derivative) and MC3 (linoleoyl derivative) have shown the highest inhibitory effects on bacterial proliferation, with MIC values of 32 μg/mL against Staphylococcus aureus. The docosahexaenoyl derivative MC5 displayed the highest anti-inflammatory activity, decreasing NO production in LPS-stimulated macrophages with an IC₅₀ value of 15.51 μg/mL higher than the positive control diclofenac (IC₅₀ of 39.71 μg/mL). All new synthesized compounds showed no anti-proliferative effects on RAW 264.7 cells. Results demonstrated as the introduction of fatty acid substituents improved the biological profile of pinocembrin. Moreover, the chemical nature of substituents significantly affects the bioactivity. These preliminary results outline the importance to investigate the synthesis of pinocembrin fatty acids derivatives as new and safe anti-microbial/anti-inflammatory agents.     

Solar thermochemical reactionsⅢ:A convenient one-pot synthesis of 1,2,4,5-tetrasubstituted imidazoles catalyzed by high surface area SiO_2 and induced by solar thermal energy

A simple,convenient and efficient method for the synthesis of 1,2,4,5-tetrasubstituted imidazole derivatives using benzoin,an aromatic aldehyde,an aromatic amine in the presence of ammonium acetate catalyzed by high surface area SiO_2 and induced by free solar thermal energy was reported.     

Molecular iodine catalyzed synthesis of tetrazolo[1,5-a]-quinoline based imidazoles as a new class of antimicrobial and antituberculosis agents

A series of some new tetrazolo[1,5-a]quinoline based tetrasubstituted imidazole derivatives 6a-1 have been synthesized by a reaction of tetrazolo[1,5-a]quinoline-4-carbaldehyde 3a-d,benzil 4,aromatic amine 5a-c and ammonium acetate in the presence of iodine through one-pot multi-component reaction(MCR) approach.All the derivatives were screened for antimicrobial and antituberculosis activities and results worth further investigations.     

Synthese und Reaktionen des 5-[p-(Dimethylamino)phenyl]-2,2-dimethyl-4-phenyl-3-oxazolins

Synthesis and Reactions of 5-[p-(Dimethylamino)phenyl]-2,2-dimethyl-4-phenyl-3-oxazoline The title compound 8 has been synthesized in a one-pot reaction of 4′-(dimethylamino)benzoin ( 4 ) with 2-propanone and NH₃. The preparation of the intermediate 4 from 3 is the first example of an acid-catalyzed transformation of the stable benzoin 3 into the corresponding less stable benzoin 4 . Structures and yields of various by-products occurring under different reaction conditions during the synthesis of 8 from 4 are given. The O-atom of the 3-oxazoline ring in 8 could be replaced by S from P₂S₅ yielding the 3-thiazoline 14 . Separation of the enantiomers of the racemate 8 could only be performed by transforming them into the trimethylanilinium salts 8b and 8c of (−)- and (+)-10-camphorsulfonic acid, respectively. Solid NaOAc in boiling toluene caused the precipitation of the 10-camphorsulfonic acids from the quaternary ammonium salts as sodium salts and the removing of the third methyl group from the quaternary ammonium salts as AcOMe to give the enantiomers (−)-(5S)- 8 and (+)-(5R)- 8 . Their absolute configurations are deduced from an X-ray analysis of 8b .     

Benzoylquinazolinone derivatives as new potential antidiabetic agents: α-Glucosidase inhibition,kinetic, and docking studies

Benzoylquinazolinone derivatives 3a–n were synthesized via a simple one-step reaction, and evaluated for in vitro α-glucosidase inhibitory activity. Compounds 3d , 3f–g , 3i , and 3m–n showed more inhibitory activity than standard drug acarbose (IC₅₀ = 750.0 ± 1.5 μM), and among them, compound 3d displayed the highest α-glucosidase inhibitory activity (IC₅₀ = 261.6 ± 0.1 μM). The kinetic analysis of the compound 3d revealed that this compound inhibited α-glucosidase in a competitive manner (K_i = 255 μM). The docking studies were applied to predict binding modes of the synthesized compounds in active site of α-glucosidase.     

One‐Pot Synthesis of 2,4,5‐Triphenyl Imidazoles from 1,2‐Diols as Key Reagents

A simple one‐pot procedure for the preparation of 2,4,5‐triphenyl imidazole derivatives is presented. The procedure involves the lead tetraacetate oxidation of 1,2‐diols to give aldehydes in situ , which then undergo a three‐component reaction with benzil and ammonium acetate to yield the imidazole derivatives.     

Development and validation of a sensitive liquid‐chromatography tandem mass spectrometry assay for mycophenolic acid and metabolites in HepaRG cell culture: Characterization of metabolism interactions between p‐cresol and mycophenolic acid

Mycophenolic acid (MPA), a frequently used immunosuppressant, exhibits large inter‐patient pharmacokinetic variability. This study (a) developed and validated a sensitive liquid chromatography–tandem mass spectrometry (LC–MS/MS) assay for MPA and metabolites [MPA glucuronide (MPAG) and acyl‐glucuronide (AcMPAG)] in the culture medium of HepaRG cells; and (b) characterized the metabolism interaction between MPA and p‐cresol (a common uremic toxin) in this in vitro model as a potential mechanism of pharmacokinetic variability. Chromatographic separation was achieved with a C₁₈ column (4.6 × 250 mm,5 μm) using a gradient elution with water and methanol (with 0.1% formic acid and 2 mm ammonium acetate). A dual ion source ionization mode with positive multiple reaction monitoring was utilized. Multiple reaction monitoring mass transitions (m/z) were: MPA (320.95 → 207.05), MPAG (514.10 → 303.20) and AcMPAG (514.10 → 207.05). MPA‐d₃ (323.95 → 210.15) and MPAG‐d₃ (517.00 → 306.10) were utilized as internal standards. The calibration curves were linear from 0.00467 to 3.2 μg/mL for MPA/MPAG and from 0.00467 to 0.1 μg/mL for AcMPAG. The assay was validated based on industry standards. p‐Cresol inhibited MPA glucuronidation (IC₅₀ ≈ 55 μm ) and increased MPA concentration (up to >2‐fold) at physiologically relevant substrate‐inhibitor concentrations (n = 3). Our findings suggested that fluctuations in p‐cresol concentrations might be in part responsible for the large pharmacokinetic variability observed for MPA in the clinic.