Synthesis and Antioxidant Capacity of Some Derivatives of Sesamol at the C-6 Position

Several synthetic approaches (aminomethylation, alkylation, condensation, etc.) have been used to synthesize derivatives based on the sesamol ( 1 ), natural phenol. The set of methods, including the study of antioxidant activity (AOA) by the ability to inhibit the initiated oxidation of animal lipids, radical scavenging activity, Fe²⁺-chelation ability, as well as a comparative assessment of membrane-protective activity under the conditions of H₂O₂-induced hemolysis of mice red blood cells (RBCs), was used to analyze the antioxidant potential of the synthesized compounds. The synthesized derivatives have demonstrated different activity in the listed test systems, and we have identified compounds which appear to be most promising for a detailed study of their pharmacological properties.     

Synthesis and Antioxidant Ability of Novel Derivatives Based on para‐Coumaric Acid Containing Isobornyl Groups

A series of novel esters and amides was synthesized on the basis of para‐coumaric acid containing isobornyl groups in ortho‐positions relative to the phenolic hydroxy group. Antioxidant properties of the obtained compounds were evaluated and compared on in vitro models: radical‐scavenging ability, antioxidant activity on a substrate containing the lipids of animal brain, cytotoxicity of red blood cells, antioxidant and membrane‐protective properties on the model of oxidative red blood cells hemolysis. Statistically significant relationship was established between the antioxidant activity of the studied compounds in model system containing animal lipids and the parameters reflecting their antioxidant properties on the model of H₂O₂‐induced hemolysis of red blood cells. It was determined that an amide with a morpholine fragment has the highest antioxidant activity. The specified derivative significantly surpassed the reference substances (parent acid, BHT) and was not inferior to the effective antioxidant 2,6‐diisobornyl‐4‐methylphenol in terms of its properties.     

Synthesis and Characterization of Novel Thiazolo[3,2‐a]pyrimidine Derivatives and Evaluation of Antioxidant and Cytotoxic Activities

A series of novel thiazolo[3,2‐a]pyrimidines were synthesized and characterized by FT‐IR, ¹H, ¹³C‐NMR and mass techniques. Their antioxidant activities were investigated by 1,1‐diphenyl‐2‐picrylhydrazyl (DPPH) radical scavenging assay and the results showed that all the synthesized compounds exhibit good antioxidant activity. In addition, it was found that any substituent on the aromatic ring of the products plays an important role in their antioxidant activity. In vitro cytotoxicity of compounds 4a – 4j was investigated using MTT cell viability assay. Among these compounds, 6‐ethyl 2,3‐dimethyl 5‐(4‐chlorophenyl)‐7‐methyl‐2,3‐dihydro‐5H‐[1,3]thiazolo[3,2‐a]pyrimidine‐2,3,6‐tricarboxylate ( 4e ) bearing a chlorine substituent displayed the highest cytotoxic effect (IC₅₀=6.26±0.6 μm ) in comparison with doxorubicin (IC₅₀=0.68±0.1 μm ) as a standard after 72 h. Therefore, it is assumed that these compounds could be used as effective antioxidant and cytotoxic agents.     

Synthesis and in Vitro Antimicrobial Activity Screening of New 3‐Acetyl‐2,5‐disubstituted‐1,3,4‐oxadiazoline Derivatives

Thirteen new 3‐acetyl‐2,5‐disubstituted‐1,3,4‐oxadiazoline derivatives were synthesized from corresponding hydrazide‐hydrazones of isonicotinic acid in the reaction with acetic anhydride. The obtained compounds were identified with the use of spectral methods (IR, ¹H‐NMR, ¹³C‐NMR, MS). In vitro antimicrobial activity screening of synthesized compounds against a panel of bacteria and fungi revealed interesting antibacterial and antifungal activity of tested 1,3,4‐oxadiazoline derivatives, which is comparable to that of commonly used antimicrobial agents.     

Synthesis and Antimicrobial Evaluation of Novel Chiral 2‐Amino‐4,5,6,7‐tetrahydrothieno[2,3‐c]pyridine Derivatives

New N‐substituted‐2‐amino‐4,5,6,7‐tetrahydrothieno[2,3‐c]pyridine derivatives were synthesized employing a convenient one‐pot three‐component method and their structures were characterized by ¹H‐NMR and single crystal X‐ray diffraction analysis. All the synthesized compounds were in vitro screened for antimicrobial activity against Gram‐positive (Sarcina lutea) and Gram‐negative bacteria (Escherichia coli). In this work, we introduced a chiral residue on the tetrahydropyridine nitrogen, the hitherto the less investigated position on this pharmacophore in order to explore the effect. The antibacterial results showed that the synthesized compounds were active only against Gram‐positive bacteria and the (R)‐enantiomers displayed a greater antimicrobial potency than their (S)‐counterparts. The structure–activity relationship here investigated may provide some interesting clues for future development of tetrahydrothienopyridine derivatives with higher antimicrobial activity.     

Synthesis and Antioxidant Activity of Carane and Pinane Based Sulfenimines and Sulfinimines

The synthesis of sulfenimines and sulfinimines has been carried out with 10‐hydroxyisocamphylthiol. The configuration of the compounds has been deduced by methods of NMR, DFT calculations and X‐ray diffraction analysis. The cytotoxic, antioxidant and membrane‐protective activity of the synthesized compounds as well as of the previously obtained sulfenimines and sulfinimines based on 4‐caranethiol have been determined.     

Design and Synthesis of Novel Thiazolo[5,4‐d]pyrimidine Derivatives as Potential Angiogenesis Inhibitors

Vascular endothelial growth factor receptor‐2 (VEGFR‐2) plays an important role in both vasculogenesis and angiogenesis. Inhibition of VEGFR‐2 has been demonstrated as a key method against tumor‐associated angiogenesis. Thiazolopyrimidine is an important analog of the purine ring, and we choose the thiazolopyrimidine scaffold as the mother nucleus. Two series of thiazolo[5,4‐d]pyrimidine derivatives were synthesized and evaluated for their antiproliferative activity. In HUVEC inhibition assay, compounds 3l (=1‐(5‐{[2‐(4‐chlorophenyl)‐5‐methyl[1,3]thiazolo[5,4‐d]pyrimidin‐7‐yl]amino}pyridin‐2‐yl)‐3‐(3,4‐dimethylphenyl)urea) and 3m (=1‐(5‐{[2‐(4‐chlorophenyl)‐5‐methyl[1,3]thiazolo[5,4‐d]pyrimidin‐7‐yl]amino}pyridin‐2‐yl)‐3‐(4‐methoxyphenyl)urea) exhibited the most potent inhibitory effect (IC₅₀=1.65 and 3.52 μm , respectively). Compound 3l also showed the best potency against VEGFR‐2 at 50 μm (98.5 %). These results suggest that further investigation of compound 3l might provide potential angiogenesis inhibitors.     

Synthesis and Evaluation of Water‐Soluble 2‐Aryl‐1‐Sulfonylpyrrolidine Derivatives as Bacterial Biofilm Formation Inhibitors

The approach to the novel 1‐[(2‐aminoethyl)sulfonyl]‐2‐arylpyrrolidines via unique intramolecular cyclization/aza‐Michael reactions of N‐(4,4‐diethoxybutyl)ethenesulfonamide have been developed, which benefits from high yields of target compounds, mild reaction conditions, usage of inexpensive and low‐toxic reagents, and allows for wide variability in both amine and aryl moieties. Biotesting with whole‐cell luminescent bacterial biosensors responding to DNA damage showed that all tested compounds are not genotoxic. Tested compounds differently affect the formation of biofilms by Vibrio aquamarinus DSM 26054. Some of the tested compounds were found to suppress the bacterial biofilms growth and thus are promising candidates for further studies.     

Design and Synthesis of Novel Cytotoxic Indole‐Thiosemicarbazone Derivatives: Biological Evaluation and Docking Study

In this work, two novel series of indole‐thiosemicarbazone derivatives were designed, synthesized, and evaluated for their cytotoxic activity against MCF‐7, A‐549, and Hep‐G2 cell lines in comparison to etoposide and colchicine as the reference drugs. Generally, the synthesized compounds showed better cytotoxicity towards A‐549 and Hep‐G2 than MCF‐7. Among them, (2E)‐2‐{[2‐(4‐chlorophenyl)‐1H‐indol‐3‐yl]methylidene}‐N‐(4‐methoxyphenyl)hydrazinecarbothioamide ( 8l ) was found to be the most potent compound against A‐549 and Hep‐G2, at least three times more potent than etoposide. The morphological analysis by the acridine orange/ethidium bromide double staining test and flow cytometry analysis indicated that compound 8l induced apoptosis in A‐549 cells. Moreover, molecular docking methodology was exploited to elucidate the details of molecular interactions of the studied compounds with putative targets.     

Synthesis and Antimicrobial Properties of Novel Phosphonium Salts Bearing 1,4‐Dihydroxyaryl Fragment

A versatile two‐step pathway to the synthesis of triaryl(2,5‐dihydroxy‐6‐methyl‐3‐(propan‐2‐yl)phenyl)‐ and triaryl(1,4‐dihydroxynaphthyl)phosphonium salts from triarylphosphonium trifluoroacetates was developed. The reaction proceeds under mild conditions (20 °C, CH₂Cl₂) with high yields (88–95 %). Some representatives of this series possess low hemolytic and high bactericidal activity against Gram‐positive bacteria.     

Synthesis and Antioxidant Properties of Psoralen Derivatives

Five psoralen derivatives were synthesized and the structures of them were characterized by ¹H-NMR, ¹³C-NMR, and IR. The antioxidant properties of the compounds were tested by inhibiting the free radical-initiated DNA oxidation and scavenging the radical reaction. The results showed that the effective stoichiometric factors (n) of the compounds V and IV could reach 2.00 and 2.11 in the system of inhibiting the DNA oxidation reaction initiated by 2,2′-Azobis(2-methylpropionamidine) dihydrochloride (AAPH). In the inhibition of ⋅OH-oxidation of the DNA system, compounds I ~ V showed antioxidant properties. The thiobarbituric acid absorbance (TBARS) percentages of compounds IV and V were 76.19 % and 78.84 %. Compounds I ~ V could also inhibit Cu²⁺/GSH-oxidation of DNA, and all compounds exhibited good antioxidant properties except compound II (94.00 %). All the five compounds were able to trap diammonium 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonate) salt radical (ABTS⁺⋅), 2,2-diphenyl-1-picrylhydrazyl radical (DPPH⋅) and 2,6-di-tert-butyl-alpha-(3,5-di-tert-butyl-4-oxo-2,5-cyclohexadien-p-tolylox radical (galvinoxyl⋅). The ability of compounds I ~ V to scavenge those free radicals can be measured by the k values. The k values ranged from 0.07 to 0.82 in scavenging ABTS⁺⋅, galvinoxyl, and DPPH radicals, respectively.     

Synthesis and Biological Activity of New 4‐tert‐Butylcyclohexanone Derivatives

In the synthesis performed in this study, derivatives of 4‐tert‐butylcyclohexanone 1 were obtained using typical reactions of organic synthesis. The bioactivity of the selected compounds was evaluated. 1‐(Bromomethyl)‐8‐tert‐butyl‐2‐oxaspiro[4.5]decan‐3‐one ( 5 ) was characterized by attractant properties against larvae and a weak feeding deterrent activity against adults of Alphitobius diaperinus Panzer . This bromolactone was a moderate antifeedant towards Myzus persicae Sulzer . In addition, ethyl (4‐tert‐butylcyclohexylidene)acetate ( 2 ) and bromolactone 5 displayed antibacterial activity. The strongest bacteriostatic effect was observed against Gram‐positive strains: Bacillus subtilis and Staphylococcus aureus. The bromolactone 5 also limited the growth of Escherichia coli strain.     

Antioxidant Properties of Ethyl Vanillin in Vitro and in Vivo

We systematically evaluated the antioxidant activity of ethyl vanillin, a vanillin analog, as compared with the activities of vanillin and other vanillin analogs using multiple assay systems. Ethyl vanillin and vanillin exerted stronger antioxidant effects than did vanillyl alcohol or vanillic acid in the oxygen radical absorbance capacity (ORAC) assay, although the antioxidant activities of vanillyl alcohol and vanillic acid were clearly superior to those of ethyl vanillin and vanillin in the three model radical assays. The antioxidant activity of ethyl vanillin was much stronger than that of vanillin in the oxidative hemolysis inhibition assay, but was the same as that of vanillin in the ORAC assay. Oral administration of ethyl vanillin to mice increased the concentration of ethyl vanillic acid, and effectively raised antioxidant activity in the plasma as compared to the effect of vanillin. These data suggest that the antioxidant activity of ethyl vanillin might be more beneficial than has been thought in daily health practice.     

Synthesis of Disulfide‐Bridged N‐Phenyl‐N′‐(alkyl/aryl/heteroaryl)urea Derivatives and Evaluation of Their Antimicrobial Activities

The discovery of new antimicrobial agents is extremely needed to overcome multidrug‐resistant bacterial and tuberculosis infections. In the present study, eight novel substituted urea derivatives ( 10a – 10h ) containing disulfide bond were designed, synthesized and screened for their in vitro antimicrobial activities on standard strains of Gram‐positive and Gram‐negative bacteria as well as on Mycobacterium tuberculosis. According to the obtained results, antibacterial effects of the compounds were found to be considerably better than their antimycobacterial activities along with their weak cytotoxic effects. Molecular docking studies were performed to gain insights into the antibacterial activity mechanism of the synthesized compounds. The interactions and the orientation of compound 10a (1,1′‐((disulfanediylbis(methylene))bis(2,1‐phenylene))bis(3‐phenylurea)) were found to be highly similar to the original ligand within the binding pocket E. faecalis β‐ketoacyl acyl carrier protein synthase III (FabH). Finally, a theoretical study was established to predict the physicochemical properties of the compounds.     

Synthesis and Biological Evaluation of Novel 1‐(4‐(Hydroxy(1‐oxo‐1,3‐dihydro‐2H‐inden‐2‐ylidene)methyl)phenyl)‐3‐phenylurea Derivatives

A series of novel phenylurea containing 2‐benzoylindan‐1‐one derivatives 3a  –  3j were synthesized from the reaction of phenylurea‐substituted acetophenones 1a  –  1j with phthalaldehyde 2 under mild reaction conditions in good yields. All synthesized compounds were characterized by spectroscopic methods. The obtained compounds ( 3a  –  3j ) were evaluated for anticancer activity against HeLa and C6 cell lines. Antiproliferative activity was determined by the BrdU proliferation ELISA assay, 3f and 3g were found to be most active compounds. The compounds were also screened for antimicrobial activity and all compounds showed remarkable activity against used microorganisms.     

Synthesis and Activity Evaluation of Nasopharyngeal Carcinoma Inhibitors Based on 6‐(Pyrimidin‐4‐yl)‐1H‐indazole

Human nasopharyngeal carcinoma is a common head and neck malignancy with high incidence in Southeast Asia and Southern China. It is necessary to develop safe, effective and inexpensive anticancer agents to improve the therapeutics of patients with nasopharyngeal carcinoma. A series of small molecular compounds based on 6‐(pyrimidin‐4‐yl)‐1H‐indazole were synthesized and evaluated for antiproliferative activities against human nasopharyngeal carcinoma cell lines SUNE1. Compounds 6b , 6c , 6e and 6l showed potent antiproliferative activities similar to positive control drug cisplatin in vitro with lower nephrotoxicity than it. N‐[4‐(1H‐Indazol‐6‐yl)pyrimidin‐2‐yl]benzene‐1,3‐diamine ( 6l ) was selected for further study. It was found that 6l induced mitochondria‐mediated apoptosis and G₂/M phase arrest in SUNE1 cells. Furthermore, compound 6l at 10 mg/kg can suppress the growth of an implanted SUNE1 xenograft with a TGI% (tumor growth inhibition) value of 50 % and did not cause serious side effects in BALB/c nude mice. This study suggests that 6‐(pyrimidin‐4‐yl)‐1H‐indazole derivatives are a series of small molecule compounds with anti‐nasopharyngeal carcinoma activities.     

Synthesis and Immunostimulating Properties of Novel Adamant‐1‐yl Tripeptides

The aim of this work was to prepare L ‐ and D ‐(adamant‐1‐yl)‐Gly‐L ‐Ala‐D ‐isoGln peptides in order to study their adjuvant (immunostimulating) activities. Adjuvant activity of adamant‐1‐yl tripeptides was tested in the mouse model using ovalbumin as an antigen and in comparison to the peptidoglycan monomer (PGM; β‐D ‐GlcNAc‐(1→4)‐D ‐MurNAc‐L ‐Ala‐D ‐isoGln‐mesoDAP(εNH₂)‐D ‐Ala‐D ‐Ala) and structurally related adamant‐2‐yl tripeptides.     

Synthesis,Anticonvulsant Activity and Metabolism of 4‐chlor‐3‐methylphenoxyethylamine Derivatives of Trans‐2‐aminocyclohexan‐1‐ol

In this study, we report the synthesis, spectral characterization, antiepileptic activity and biotransformation of three new, chiral, N‐aminoalkyl derivatives of trans – 2 aminocyclohexan‐1‐ol: 1 (R enantiomer), 2 (S enantiomer) and 3 (racemate). Antiepileptic activity of the titled compounds was studied using MES and scMet. Moreover, in this study, the biotransformation of 1 , 2 and 3 in microbial model (Cunninghamella), liver microsomal assay as well as in silico studies (MetaSite) was evaluated. Studies have indicated that 1 , 2 and 3 have good antiepileptic activity in vivo, comparable to valproate. Biotransformation assays showed that the most probable metabolite (indicated in every tested assays) was M1 . The microbial model as well as in silico study showed no difference in biotransformation between tested enantiomers. However, in a rat liver microsomal study compound 1 and 2 (R and S enantiomer) had different main metabolite – M2 for 1 and M1 for 2 . MS/MS fragmentation allowed us to predict the structures of obtained metabolites, which were in agreement with 1°alcohol ( M1 ) and carboxylic acid ( M2 ). Our research has shown that microbial model, microsomal assay, and computational methods can be included as useful and reliable tools in early ADME‐Tox assays in the process of developing new drug candidates. Chirality 27:163–169, 2015. © 2014 Wiley Periodicals, Inc.     

Design,Synthesis, and Cytotoxic Activity of 3‐Aryl‐N‐hydroxy‐2‐(sulfonamido)propanamides in HepG2, HT‐1080, KB,and MCF‐7 Cells

A new series of (sulfonamido)propanamides ( 6a1 – 6a13 , 6b1 – 6b15 , 7c1 – 7c5 , 6d1 – 6d5 , 6e1 – 6e6 ) was designed and synthesized. All the synthesized compounds were characterized by NMR and mass spectrometry. The target compounds were evaluated for their in vitro cytotoxic activity against hepatocellular carcinoma (HepG2), fibrosarcoma (HT‐1080), mouth epidermal carcinoma (KB), and breast adenocarcinoma (MCF‐7) cell lines with the sulforhodamine B (SRB) assay, with gemcitabine and mitomycin C as positive controls. Most of these compounds exhibit a more potent cytotoxic effect than the positive control group on various cancer cell lines and the most potent compound, 6a7 , shows the IC₅₀ values of 29.78±0.516 μm , 30.70±0.61 μm , and 64.89±3.09 μm in HepG2, HT‐1080, KB, and MCF‐7 cell lines, respectively. Thus, these compounds with potent cytotoxic activity have potential for development as new chemotherapy agents.     

Synthesis and Antibacterial Evaluation of Mannich Bases Derived from 1,2,4‐Triazole

The series of novel Mannich bases were synthesized and evaluated for their in vitro antibacterial activity against Gram‐positive and Gram‐negative bacterial strains. The results showed that all compounds were less active than the drugs used as reference, but some of them had moderate potency against Staphylococcus epidermidis ATCC 12228 and Bacillus subtilis ATCC 6633. The presence of a phenyl ring in the position 4 of piperazine seems to be necessary for antibacterial activity in this class of compounds.