2a 2f Research Articles

1,2,3‐Triazole analogs with bulky and conformationally rigid substructures: Synthesis and in vitro evaluation as DPP‐4 inhibitors

AbstractNovel 1,2,3‐triazole analogs with bulky and conformationally rigid azacyclic/azabicyclic amine and alcohol substructures at the C4 position were synthesized and evaluated for their inhibitory activities against human dipeptidyl peptidase‐4 enzyme. The synthesized 1,2,3‐triazole analogs (2a–2f) exhibited moderate in vitro hDPP‐4 inhibitory activities (0.32–>2.0 μM) in comparison to the analog with the C4 tert‐Bu group (0.24 μM). However, the reduced bioactivity of the 1,2,3‐triazole analogs with bulky and conformationally rigid substructures might be attributed to the lower‐than‐anticipated van der Waals interactions of the introduced heterocycles. Another plausible explanation for the reduced activity could be due to the role of two other factors (π–π interaction and H‐bonding) in influencing the interaction of the analogs with the key amino residues in the pocket of the enzyme. Further research is encouraged to explore the role of these factors in deciding the enzyme‐inhibiting activities of the C4 substituted 1,2,3‐triazole analogs.

Synthesis of 1-hydroxy-3-O-substituted xanthone derivatives and their structure-activity relationship on acetylcholinesterase inhibitory effect

This study focused on the synthesis of 1,3-dihydroxyxanthone (1) and its new derivatives with alkyl (2a–2f), alkenyl (2 g–2k), alkynyl (2 l–2n), and alkylated phenyl (2o–2r) groups at C3 position. The structures of these compounds were confirmed by MS, NMR, and FTIR spectroscopic data. All the substituted xanthones (2a–2r) showed significantly stronger acetylcholinesterase (AChE) inhibitory activities than 1. Compounds 2g and 2j exhibited the strongest activities with the IC50 values of 20.8 and 21.5 μM and their enzyme kinetic analyses indicated a mixed-mode inhibition. Molecular docking study revealed that 2g binds favourably to the active site of AChE via π–π stacking and hydrogen bonding from the xanthone ring, in addition to π-alkyl interaction from the substituent group. These xanthone derivatives are potential lead compounds to be further developed into Alzheimer’s disease drugs.

“On Water” Effect for Green Click Reaction: Spontaneous Polymerization of Activated Alkyne with “Inert” Aromatic Amine in Aqueous Media

“On Water” Effect for Green Click Reaction: Spontaneous Polymerization of Activated Alkyne with “Inert” Aromatic Amine in Aqueous Media

Synthesis and Structural Study of Amidrazone Derived Pyrrole-2,5-Dione Derivatives: Potential Anti-Inflammatory Agents.

1H-pyrrole-2,5-dione derivatives are known for their wide range of pharmacological properties, including anti-inflammatory and antimicrobial activities. This study aimed to synthesize new 3,4-dimethyl-1H-pyrrole-2,5-dione derivatives 2a–2f in the reaction of N3-substituted amidrazones with 2,3-dimethylmaleic anhydride and evaluate their structural and biological properties. Compounds 2a–2f were studied by the 1H-13C NMR two-dimensional techniques (HMQC, HMBC) and single-crystal X-ray diffraction (derivatives 2a and 2d). The anti-inflammatory activity of compounds 2a–2f was examined by both an anti-proliferative study and a production study on the inhibition of pro-inflammatory cytokines (IL-6 and TNF-α) in anti-CD3 antibody- or lipopolysaccharide-stimulated human peripheral blood mononuclear cell (PBMC) cultures. The antibacterial activity of compounds 2a–2f against Staphylococcus aureus, Enterococcus faecalis, Micrococcus luteus, Esherichia coli, Pseudomonas aeruginosa, Yersinia enterocolitica, Mycobacterium smegmatis and Nocardia corralina strains was determined using the broth microdilution method. Structural studies of 2a–2f revealed the presence of distinct Z and E stereoisomers in the solid state and the solution. All compounds significantly inhibited the proliferation of PBMCs in anti-CD3-stimulated cultures. The strongest effect was observed for derivatives 2a–2d. The strongest inhibition of pro-inflammatory cytokine production was observed for the most promising anti-inflammatory compound 2a.

Kinetic study on pyridinolysis of aryl benzenesulfonates: factors governing regioselectivity and reaction mechanism

A kinetic study is reported for reactions of 2,4-dinitrophenyl X-substituted-benzenesulfonates (1a–1f) and Y-substituted-phenyl benzenesulfonates (2a–2f) with Z-substituted-pyridines. The reactions proceed through S–O and C–O bond scissions competitively. The Yukawa–Tsuno plot for the reactions of 1a–1f with 4-oxypyridine (S–O bond fission) exhibits an excellent linearity. The Brønsted-type plot for the reactions of 2,4-dinitrophenyl benzenesulfonate (1d) with pyridines (S–O bond fission) is also linear with βnuc = 0.62. The Brønsted-type plot for the reactions of 2a–2f with 4-oxypyridines (S–O bond fission) is linear with βlg = –1.17. Thus, the reactions have been concluded to proceed through a concerted mechanism, in which leaving-group expulsion is significantly more advanced than bond formation between the electrophilic center and nucleophile at the transition state. The Hammett plot for the reactions of 1a–1f with 4-oxypyridine (C–O bond fission) exhibits scattered points with ρX = 0.98. The Brønsted-type plot for the reactions of 1d with Z-substituted-pyridines (C–O bond fission) results in an excellent linear correlation with βnuc = 0.38. Thus, the reactions (C–O bond fission) have been concluded to proceed through a stepwise mechanism with a Meisenheimer complex, in which expulsion of the leaving group occurs after the rate-determining step. Factors governing regioselectivity and reaction mechanism are discussed.

N-Arylation of Protected and Unprotected 5-Bromo-2-aminobenzimidazole as Organic Material: Non-Linear Optical (NLO) Properties and Structural Feature Determination through Computational Approach.

The interest in the NLO response of organic compounds is growing rapidly, due to the ease of synthesis, availability, and low loss. Here, in this study, Cu(II)-catalyzed selective N-arylation of 2-aminobenzimidazoles derivatives were achieved in the presence of different bases Et3N/TMEDA, solvents DCM/MeOH/H2O, and various aryl boronic acids under open atmospheric conditions. Two different copper-catalyzed pathways were selected for N-arylation in the presence of active nucleophilic sites, providing a unique tool for the preparation of NLO materials, C-NH (aryl) derivatives of 2-aminobenzimidazoles with protection and without protection of NH2 group. In addition to NMR analysis, all synthesized derivatives (1a–1f and 2a–2f) of 5-bromo-2-aminobenzimidazole (1) were computed for their non-linear optical (NLO) properties and reactivity descriptor parameters. Frontier molecular orbital (FMO) analysis was performed to get information about the electronic properties and reactivity of synthesized compounds.

Synthesis and biological activity evaluation of some new mixed azines appended tetrahydro-1,2,4-triazines

A series of 6-acetyl-2,4-diaryl-2,3,4,5-tetrahydro-1,2,4-triazines (2a–2f) was synthesized by double Mannich reaction of the hydrazone 1a or 1b with formaldehyde and the appropriate amine. A similar reaction of 1a with the appropriate diamine afforded the bis(tetrahydro-triazines) 3a–b, and 4a–b. Whereas, the 6-cinnamoyl derivatives 5a-c were obtained by the reaction of 2a with the appropriate aldehyde. The hydrazone 7, derived from 2a, was treated with the appropriate aldehyde or ketone to afford the mixed azines 8–12 and 13–16. The biological activity, antibacterial, antifungal and antioxidants of the most newly synthesized compounds of these derivatives were screened. Compounds 2b, 3a and 7 revealed the best results against all screened biological activity

Anti-tubercular activity and molecular docking studies of indolizine derivatives targeting mycobacterial InhA enzyme

A series of 1,2,3-trisubstituted indolizines (2a–2f, 3a–3d, and 4a–4c) were screened for in vitro whole-cell anti-tubercular activity against the susceptible H37Rv and multidrug-resistant (MDR) Mycobacterium tuberculosis (MTB) strains. Compounds 2b–2d, 3a–3d, and 4a–4c were active against the H37Rv-MTB strain with minimum inhibitory concentration (MIC) ranging from 4 to 32 µg/mL, whereas the indolizines 4a–4c, with ethyl ester group at the 4-position of the benzoyl ring also exhibited anti-MDR-MTB activity (MIC = 16–64 µg/mL). In silico docking study revealed the enoyl-acyl carrier protein reductase (InhA) and anthranilate phosphoribosyltransferase as potential molecular targets for the indolizines. The X-ray diffraction analysis of the compound 4b was also carried out. Further, a safety study (in silico and in vitro) demonstrated no toxicity for these compounds. Thus, the indolizines warrant further development and may represent a novel promising class of InhA inhibitors and multi-targeting agents to combat drug-sensitive and drug-resistant MTB strains.

Alkenylation of ortho-palladated phenylglycine: synthesis of stilbene derivatives and 3-aryl-isoquinoline-1-carboxylates

The ortho-palladated phenylglycine derivative [Pd(µ-Cl)(C6H4C(H)(CO2Me)NH2-C,N)]2 (1) reacts with substituted styrenes R1C6H4CH=CH2 (2a–2f) to give two different compounds as a function of the reaction conditions. When the reaction was performed in chloroform under reflux, the stilbene derivatives [C6H4-1-(CH(CO2Me)(NH2))-2-(E)-(CH=CHC6H4R1)] (3a–3f) were obtained, but when the reaction was carried out in toluene under reflux, the 3-arylisoquinoline-1-carboxylates (4a–4f) were obtained instead. The method has distinct advantages over other methods in that it is simple and general, only one/two reaction steps are necessary to obtain the final product, the prefunctionalisation of the substrates is not mandatory and nor is the presence of ancillary ligands, and a regioselective mono-insertion of the alkenes is systematically observed.

Microwave Assisted Synthesis of 4-Phenylquinazolin-2(1H)-one Derivatives that Inhibit Vasopressor Tonus in Rat Thoracic Aorta.

Quinazolinones have pharmacological effects on vascular reactivity through different mechanisms. We synthesized 4-phenylquinazolin-2(1H)-one derivatives under microwave irradiation and tested them on the rat thoracic aorta. The prepared compounds 2a–2f were obtained in about 1 h with suitable yields (31–92%). All derivatives produced vasorelaxant effects with IC50 values ranging from 3.41 ± 0.65 µM to 39.72 ± 6.77 µM. Compounds 2c, 2e and 2f demonstrated the highest potency in endothelium-intact aorta rings (IC50 4.31 ± 0.90 µM, 4.94 ± 1.21 µM and 3.41 ± 0.65 µM respectively), and they achieved around 90% relaxation (30 μM). In aorta rings without an endothelium, the effect of compound 2f was abolished. Using the MTT assay to test for cell viability, only compound 2b induced cytotoxicity at the maximum concentration employed (30 µM). The results show that vasorelaxation by 4-phenylquinazolin-2(1H)-one derivatives might depend on the activation of a signalling pathway triggered by endothelium-derived factors.

Design, Synthesis, and Anticancer Activities of Cyclometalated Tris(2‐phenylpyridine)iridium(III) Complexes with Cationic Peptides at the 4′‐Position of the 2‐Phenylpyridine Ligand

We previously reported the design and synthesis of amphiphilic Ir complex–cationic peptide hybrids (2a–2f), which contain basic peptide sequences such as KKGG (K = lysine, G = glycine) at the 5′‐positions (para position with respect to the C–Ir bond) of three 2‐(4′‐tolyl)pyridine (tpy) ligands. Among them, 2c–2e induced the necrosis‐like cell death of Jurkat cells through a calcium‐dependent pathway, possibly involving a Ca2+–calmodulin (CaM) complex. Herein, we report the synthesis of amphiphilic Ir(ppy)3 complexes (ppy = 2‐phenylpyridine) containing the KKGG sequence at the 4′‐position of the ppy moiety (4a–4d) to examine the effect of the position of the cationic peptide sequence on the cytotoxicities of the complexes against Jurkat cells. The results of 3‐(4,5‐dimethly‐2‐thiazolyl)‐2,5‐diphenyl‐2H‐tetrazolium bromide (MTT) assays and a mechanistic study indicate that 4b and 4c, which contain C6 and C8 linkers, induce cell death through a calcium‐dependent pathway accompanied by membrane disruption in a manner similar to that of 2c–2e but with smaller half‐maximal effective concentration (EC50) values than those of 2c–2e. The results of the photoaffinity labeling of Jurkat cells with 5b containing a photoreactive 3‐trifluoromethyl‐3‐phenyldiazirine (TFPD) unit and co‐staining experiments with specific probes for intracellular organelles suggest that 4b and 4c bind to Ca2+–CaM and are localized in the mitochondria during cell death.

Design, Synthesis, and Biological Evaluation of Ganglioside Hp-s1 Analogues Varying at Glucosyl Moiety.

Ganglioside Hp-s1 is isolated from the ovary of sea urchin Diadema setosum. It exhibited better neuritogenic activity than GM1 in pheochromocytoma 12 cells. To explore the roles of glucosyl moiety of Hp-s1 in contributing to the neurogenic activity, we developed feasible procedures for synthesis of Hp-s1 analogues (2a-2f). The glucosyl moiety of Hp-s1 was replaced with α-glucose, α-galactose, β-galactose, α-mannose, and β-mannose, and their biological activities on SH-SY5Y cells and natural killer T (NKT) cells were evaluated. We found that the orientation of C-2 hydroxyl group at glucosyl moiety of Hp-s1 plays an important role to induce neurite outgrowth of SH-SY5Y cells. Surprisingly, compound 2d could activate NKT cells to produce interleukin 2, although it did not show great activity on neurite outgrowth of SH-SY5Y cells. In general, the Hp-s1 might be considered as a lead compound for the development of novel drugs aimed at modulating the activity of neuronal cells.

Pyrazolylbenzo[d]imidazoles as new potent and selective inhibitors of carbonic anhydrase isoforms hCA IX and XII

Novel pyrazolylbenzo[d]imidazole derivatives (2a–2f) were designed, synthesized and evaluated against four human carbonic anhydrase isoforms belonging to α family comprising of two cytosolic isoforms hCA I and II as well as two transmembrane tumor associated isoforms hCA IX and XII. Starting from these derivatives that showed high potency but low selectivity in favor of tumor associated isoforms hCA IX and XII, we investigated the impact of removing the sulfonamide group. Thus, analogs 3a–3f without sulfonamide moiety were synthesized and biological assay revealed a good activity as well as an excellent selectivity as inhibitors for tumor associated hCA IX and hCA XII and the same was analyzed by molecular docking studies.

Microwave assisted selective synthesis of (E)-1-(4-Chloro-7-hydroxy-2-aryl-2H-chromen-6-yl)-3-arylprop-2-en-1-ones and their antimicrobial activity

A series of new (E)-1-(4-chloro-7-hydroxy-2-aryl-2H-chromen-6-yl)-3-arylprop-2-en-1-ones (2a–2f) have been synthesized by selective mono cyclization of 4,6-dicinnamoyl resorcinols (1a–1f) using Vilsmeier–Haack reagent under conventional heating and microwave irradiation. The structures of the synthesized compounds have been elucidated by elemental analysis, IR, 1H NMR, 13C NMR and Mass spectral data. The synthesized compounds were tested in vitro for antimicrobial activity.

Novel N‐Substituted ((1H‐indol‐3‐yl)methylene)benzohydrazides and ((1H‐indol‐3‐yl)methylene)‐2‐phenylhydrazines: Synthesis and Antiplatelet Aggregation Activity

Based on our previous studies on antiplatelet hydrazone derivatives, some new indole‐based derivatives were designed and synthesized as potential antiplatelet agents. Synthesis of the derivatives was accomplished by substitution at the N – 1 position of indole‐3‐carboxaldehyde and reacting the resulting intermediates with either phenylhydrazine of benzoylhydrazide. The structure of the synthesized compounds was confirmed by different spectral methods such as mass spectrometry, 1H‐NMR, and IR spectroscopy. The derivatives were tested for their ability to inhibit human platelet aggregation, where arachidonic acid (AA), adenosine diphosphate ADP, and collagen were used as aggregation inducers. Compounds (2a–2f) showed considerable activity against AA‐induced platelet aggregation. Among them, compounds 2a, 2b, and 2f were the most potent derivatives with IC50 values comparable to that of aspirin as standard drug. Analysis of structure–activity relationship shows that with increased bulk of the substituents at indole N – 1, the antiplatelet activity is reduced, thus suggesting that steric hindrance at this position plays a major role in the activity of the tested compounds.

Kinetic Study on Quinuclidinolysis of O‐4‐Nitrophenyl X‐substituted Thionobenzoates and O‐3,4‐Dinitrophenyl Thionobenzoate: Effect of Amine Nature on Reactivity and Reaction Mechanism

Second‐order rate constants (k quin) have been measured spectrophotometrically for the reactions of O‐3,4‐dinitrophenyl thionobenzoate (1a) with a series of quinuclidine derivatives and of O‐4‐nitrophenyl X‐substituted thionobenzoates (2a–2f) with quinuclidine in 80 mol% H2O/20 mol% DMSO at 25.0 ± 0.1 °C. Quinuclidine is less reactive toward the thione esters than less basic benzylamine. Steric hindrance exerted by the tertiary amine is responsible for the decreased reactivity. The Hammett plot for the reactions of 2a–2f with quinuclidine consists of two intersecting straight lines, while the Yukawa–Tsuno plot for the same reactions exhibits an excellent linear correlation with ρ X = 1.10 and r = 0.71. This indicates that the nonlinear Hammett plot is not due to a change in the rate‐determining step but is caused by ground‐state stabilization of substrates possessing an electron‐donating group in the thionobenzoyl moiety through resonance interactions. Brønsted‐type plot for the reactions of 1a with quinuclidines is linear with β nuc = 0.89, which is typical for reactions reported to proceed through a stepwise mechanism. However, the reactions have been concluded to proceed through a forced concerted mechanism. Instability of a plausible intermediate T± forces the reactions to proceed through such a mechanism.

Synthesis and antimicrobial activity of some new 4H-pyrrolo[1,2-a]benzimidazoles

Some new 4H-pyrrolo[1,2-a]benzimidazoles(2a–2f) have been synthesized. The structures of these compounds were confirmed by IR, 1H NMR, mass spectroscopy and elemental analysis. Compound 2a was further confirmed by X-ray diffraction. The in vitro antimicrobial activities of these compounds were determined against some gram-positive bacteria, gram-negative bacteria and fungi and their drug-resistant isolates in comparison with standard drugs. Antimicrobial results indicate that compounds 2c, 2d and 2e show moderately active antibacterial properties, their minimum inhibitory concentrations are from 12.5 μg/mL to 125 μg/mL. In the series, the most active compound against C. albicans is compound 2f with an MIC value of 31.25 μg/mL.

Synthesis of Novel Pyridopyridazin-3(2H)-one Derivatives and Evaluation of Their Cytotoxic Activity against MCF-7 Cells

A series of pyridopyridazin-3(2H)-one derivatives was synthesized in two facile steps. Mannich-type three-component condensation afforded the 2,6-diaryl piperidin-4-one derivatives, which underwent intramolecular cyclization in the presence of hydrazine or phenylhydrazine to yield the corresponding pyridopyridazin-3(2H)-one derivatives. All the derivatives of pyridopyridazin-3(2H)-one, except 3e and 3f, showed moderate activity against human breast adenocarcinoma (MCF-7) cells. The higher degree of inhibition of MCF-7 cell proliferation shown by 2a–2f indicates the significance of the amide proton in pyridopyridazin-3(2H)-one derivatives.

Copper(II) Complexes of 2-(Methylthiomethyl)anilines: Spectral and Structural Properties and In Vitro Antimicrobial Activity

Copper(II) complexes of 2-(methylthiomethyl)anilines (1a–1f) have been obtained and characterized by elemental analyses, IR, electronic spectra, conductivity, and X-ray crystallography. The complexes (2a–2f) have the structural formula [CuCl2L] with the bidentate ligand coordinating through sulfur and nitrogen. The single crystal X-ray diffraction data reveal that the copper complex (2f) has a tetragonally distorted octahedral structure with long Cu–Cl equatorial bonds. Magnetic susceptibility measurements indicate the availability of one unpaired electron in the complexes and the conductivity measurements in DMF show their behaviour as nonelectrolytes. The solid reflectance spectra and the electronic spectra of the complexes in DMSO were determined. The ligands and their copper complexes were screened for in vitro antimicrobial activity against S. aureus, B. subtilis, E. coli, and C. albicans. The methoxysubstituted complex (2c) showed more promising antibacterial activity against S. aureus and B. subtilis than other compounds at the concentration tested.

ChemInform Abstract: Ruthenium Catalyzed Hydroaminoalkylation of Isoprene via Transfer Hydrogenation: Byproduct‐Free Prenylation of Hydantoins.

AbstractIsoprene is added to arylated hydantoins in the absence of a directing group.