Compounds 4i Research Articles

Design, synthesis, characterization, molecular docking studies and anticancer activity evaluation of novel hydrazinecarbothioamide, 1,2,4-triazole-3-thione, 4-thiazolidinone and 1,3,4-oxadiazole derivatives

A series of novel hydrazinecarbothioamide, 1,2,4-triazole-3-thione, 4-thiazolidinone and 1,3,4-oxadiazole derivatives were synthesized and evaluated for their cytotoxic activity against A549 lung adenocarcinoma cells and L929 normal mouse fibroblast cell line. The structural elucidation of the compounds was performed and verified by IR spectroscopy, 1H-NMR, 13C-NMR, mass and elemental analysis. Compound 3a, 3b, 3c, 3d, 3e, 3g and 3i displayed the best anticancer activity against A-549 cell line. The anticancer activities of 3a, 3c, 3d, 3e, 3g and 3i were determined as better than the positive control Cisplatin. In addition to the in vitro analysis, molecular docking studies were employed to explore the possible binding interactions of the title compounds with B-DNA (PDB ID: 1BNA) dodecamer d(CGCGAATTCGCG)2. Structure-activity relationships, as well as virtual ADME studies, were carried out and a relationship between biological, electronic, and physicochemical qualifications of the target compounds was determined. Consequently, these derivatives present a leading structure for future drug development due to their straightforward synthesis and relevant bioactivity.

Design and synthesis of novel benzimidazole-iminosugars linked a substituted phenyl group and their inhibitory activities against β-glucosidase

A series of novel benzimidazole-iminosugars linked a (substuituted) phenyl group on benzene ring of benzimidazole 5(a-p) and 6(a-p) have been rationally designed and conveniently synthesized through Suzuki coupling reaction in high yields. All compounds have been evaluated for their inhibitory activities against β-glucosidase (almond). Six compounds 5d, 6d, 6e, 6i, 6n, and 6p showed more significant inhibitory activities with IC50 values in the range of 0.03–0.08 μM, almost 10-fold improved than that of the parent analogue 4, and much higher than that of the positive control castanospermine. The additional phenyl ring and the electron donating groups on it would be beneficial for the activity. Compounds 6d, 6n, and 4 had been chosen to be tested for their inhibition types against β-glucosidase. Interestingly, three compounds have different inhibition types although they had very similar structure. Their Ki values were calculated to be 0.02 ± 0.01 μM, 0.02 ± 0.01 μM, and 0.66 ± 0.14 μM, respectively. The equilibrium dissociation constant (KD) for 6d, 6n, and 4 and β-glucosidase was 0.04 μM, 0.03 μM and 0.45 μM by the ITC-based assay, respectively. Molecular docking work suggests that such benzimidazole-iminosugars derivatives might bind to the active site of β-glucosidase mainly through hydrogen bonds, the additional phenyl ring towards the solvent-exposed region played an important effect on their inhibitory activity against β-glucosidase.

Linker optimization of HEPT derivatives as potent non-nucleoside HIV-1 reverse transcriptase inhibitors: From S=O to CHOR

A novel series of CHOR-HEPT non-nucleoside HIV-1 reverse transcriptase inhibitors were developed by means of structure-based design strategy based on compound 6 reported previously by our group. Most of these compounds showed moderate to good activity toward wild-type HIV-1 strain with EC50 values in the range of 0.18–51.88 µmol/L and SI values in the range of 4–907. The compound 14aj with a CHOH linker and compound 13i with a CHOTMS linker in this series exhibited improved anti-HIV-1 activity (EC50 = 0.18 µmol/L, and 0.20 µmol/L) with higher selectivity (SI = 907, and 665) as comparison with the lead compound 6 (EC50 = 0.59 µmol/L, SI = 9). These two compounds 14aj and 13i were more sensitive than 6 toward clinically relevant mutant L100I, K103N and E138K viruses, which were further evaluated for their activity against wild-type reverse transcriptase and displayed a good correlation with the cell-based activity. Preliminary molecular modeling investigations provided insight for further structural optimization of HEPT.

Synthesis and biological evaluation of novel pentanediamide derivatives as S-adenosyl-l-homocysteine hydrolase inhibitors

A series of novel pentanediamide derivatives were designed, synthesized and evaluated as S-adenosyl-l-homocysteine hydrolase (SAHase) inhibitors in this study. Some compounds showed good inhibitory activity against SAHase. The optimal compound 7i showed good inhibitory activity against SAHase with IC50 value of 3.58 ± 0.19 μM, cytotoxicity with IC50 values ranging from 13.16 ± 1.44 to 21.23 ± 0.73 μM against four tumor cell lines (MCF-7, A549, MGC-803, Hela) and very weak cytotoxicity (IC50 = 84.22 ± 1.89 μM) on normal LO2 cells. In addition, compound 7i showed potency against respiratory syncytial virus with EC50 value of 27.4 μM and selectivity index of 6.84. Further molecular simulation study suggested that compound 7i had good ADMET properties, and strongly binds to the active site of SAHase. In summary, compound 7i could serve as a new lead compound for further screening novel non-adenosine SAHase inhibitors.

Synthesis of novel 4,7-disubstituted quinoline derivatives as autophagy inducing agents via targeting stabilization of ATG5

A series of new 4,7-disubstituted quinoline derivatives was designed, synthesized and evaluated for their antiproliferative activity. The results demonstrated that compounds 10c, 10g, 10i, 10j and 10k displayed potent antiproliferative activity with IC50 value of lower than 5.0 μM against human tumor cell lines, and N-(3-nitrophenyl)-7-((3,4,5-trimethoxybenzyl)oxy)quinoline -4-amine 10k was found to be the most potent antiproliferative agent against HCT-116, HepG2, BCG-823, A549 and A2780 cell lines with IC50 values of 0.35, 1.98, 0.60, 0.39 and 0.67 μM, respectively. The antitumor efficacy of the representative compound 10k in mice was also evaluated, and the results showed that compound 10k effectively inhibited tumor growth and decreased tumor weight in animal models. Further investigation on mechanism of action indicated that compound 10k could inhibit colorectal cancer growth through inducing autophagy via excessively targeting stabilization of ATG5. Therefore, these quinoline derivatives are a new class of molecules that have the potential to be developed as new antitumor drugs.

Synthesis, molecular docking, and biological evaluation of methyl-5-(hydroxyimino)-3-(aryl-substituted)hexanoate derivatives

Beta-aryl keto hexanoic acids (5a-l) were synthesized efficiently, followed by esterification that afforded beta-aryl keto methylhexanoates (6a-l). The chemo-selective ketoxime beta-aryl methyl hexanoates (7a-l) were isolated in good yields. Spectroscopic methods were used to characterize the obtained moieties. The antioxidant, anti-inflammatory, and antibacterial properties of the effectively synthesized compounds 7a-l were also investigated. The anti-inflammatory activity of the compounds 7c, 7f, 7i, and 7l was excellent, with a low IC50 value at micromolar concentration, which was much better than the reference diclofenac. All synthesized compounds 7a-l were assessed for their in vitro antibacterial activity against S. aureus, B. subtilis and E. coli. Most of the compounds exhibited promising activity against Gram-positive bacterial strain, compound 7i showed excellent activity compared to standard streptomycin and in the case of E. coli, compounds 7b, 7c, 7j, 7k and 7l have shown moderate activity. Further, the cytotoxic activities of the compounds were assessed against lung cancer cells (A549) by using MTT assay. The possible interaction mechanism of the molecules 7c and 7g with Gram-negative strain E. coli DNA gyrase B in complex with PDB ID: 4DUH was studied.

An efficient p‐TSA catalyzed synthesis of some new substituted‐(5‐hydroxy‐3‐phenylisoxazol‐4‐yl)‐1,3‐dimethyl‐1H‐chromeno[2,3‐d]pyrimidine‐2,4(3H,5H)‐dione/3,3‐dimethyl‐2H‐xanthen‐1(9H)‐one scaffolds and evaluation of their pharmacological and computational investigations

We have developed an easy and efficient protocol for the synthesis of a series of some novel substituted-(5-hydroxy-3-phenylisoxazol-4-yl)-1,3-dimethyl-1H-chromeno[2,3-d]pyrimidine-2,4(3H,5H)-dione/3,3-dimethyl-2H-xanthen-1(9H)-one derivatives (4a–j) via p-TSA catalyzed reaction of 1,3-dimethylbarbituric acid/dimedone, substituted salicylaldehyde/2-hydroxy-nepthaldehyde and 3-phenyl-5-isoxazolone was administered in refluxed temperature in the presence of aqueous ethanol. All the obtained compounds were evaluated for their therapeutic effect using pharmacological and computational investigations, and structures were confirmed using analytical and spectroscopic techniques. Absorption spectra were recorded in six different solvents such as polar protic, polar aprotic, and nonpolar solvents, λmax of all the compounds are appeared at bathochromic shift towards the longer wavelength due to the π-π* & n-π* transitions. The results of pharmacological investigations revealed that the compounds 4c, 4e, and 4h possess excellent cytotoxicity efficacy, and compounds 4c, 4d, 4h, and 4i have shown better anti-TB efficiency. The SAR study shows the importance of the electron-withdrawing group and additional phenyl nucleus enhancing the biological potency of the compounds. The results of the in silico molecular docking studies revealed that the compounds 4c and 4h effectively interacted with P38 MAP kinase (-10.9 kcal/mol) and InhA-Enoyl-Acyl Carrier Protein Reductase (-11.0 kcal/mol), respectively. Further, the molecular dynamics (MD) simulation studies revealed that the compounds 4c and 4h stabilized the macromolecular structures in terms of RMSD, RMSF, the Radius of gyration, and SASA compared to their unbound and standard compound bound structures. DFT study suggested that the compounds are chemically and biologically more reactive due to less energy gap.

Synthesis and Biological Evaluation of 5-Fluoro-2-Oxindole Derivatives as Potential α-Glucosidase Inhibitors

α-Glucosidase inhibitors are known to prevent the digestion of carbohydrates and reduce the impact of carbohydrates on blood glucose. To develop novel α-glucosidase inhibitors, a series of 5-fluoro-2-oxindole derivatives (3a ∼ 3v) were synthesized, and their α-glucosidase inhibitory activities were investigated. Biological assessment results showed that most synthesized compounds presented potential inhibition on α-glucosidase. Among them, compounds 3d, 3f, and 3i exhibited much better inhibitory activity with IC50 values of 49.89 ± 1.16 μM, 35.83 ± 0.98 μM, and 56.87 ± 0.42 μM, respectively, which were about 10 ∼ 15 folds higher than acarbose (IC50 = 569.43 ± 43.72 μM). A kinetic mechanism study revealed that compounds 3d, 3f, and 3i inhibited the α-glucosidase in a reversible and mixed manner. Molecular docking was carried out to simulate the affinity between the compound and α-glucosidase.

Wang resin catalyzed sonochemical synthesis of dihydropyrano[2,3-c]pyrazole derivatives and their interactions with SIRT1

The pyrano[2,3-c]pyrazole framework was explored for the design and synthesis of compounds as potential inhibitors of SIRT1. The feasibility of this strategy was reasoned by the unique structural features of this scaffold and the reported cytotoxicity of compounds containing this framework. The sonochemical synthesis of target compounds was accomplished by using the Wang resin (Wang-OSO3H) as a recoverable catalyst under eco-friendly conditions. Thus, the desired 4-substituted 6-amino-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile derivatives were prepared via a 4-component reaction of β-ketoester, hydrazine, aldehyde and malononitrile in pure water in good yields. The recyclability of the catalyst was demonstrated successfully. All the synthesized compounds were initially assessed in silico against the targeted protein i.e. hSIRT1 that indicated compound 5i and 5l along with several other compounds as possible inhibitors. Both of these compounds participated in two vital H-bond interactions with the residue GLN345 and ASN346 in silico that was reflected in their estimated total energy. In vitro assessment of these pyrano[2,3-c]pyrazoles against SIRT1 revealed encouraging inhibitory activities (> 50% inhibition) that was in agreement with the results of docking studies. Indeed, 5i and 5l were identified as the most active compounds in this series. The Structure-Activity-Relationship (SAR) study suggested important role of the C-4 aryl substituent along with the N-1 phenyl ring of the pyrano[2,3-c]pyrazole moiety in the SIRT1 inhibitory activities of this class of compounds. Thus, a OH or Cl group at the p-position of the C-4 benzene ring together with the N-1 phenyl moiety appeared to be beneficial for activity. Overall, the initial design and then sonochemical synthesis followed by in silico as well as in vitro studies allowed identification of pyrano[2,3-c]pyrazole based small molecules as potential inhibitors of SIRT1.

Synthesis and evaluation of cerebroprotective activity of novel 6,7-dimethoxyquinazolin-4(3H)-one derivatives containing residues of amino acids and dipeptides

Neurodegenerative processes of the central nervous system are an important socially significant problem of modern society. They cause many diseases, such as Alzheimer's disease and cerebral ischemia, which significantly reduce the quality of human life and can lead to disability or death. The aim of this study was to synthesize novel 6,7-dimethoxyquinazolin-4(3H)-one derivatives with the remains of neuroactive amino acids and dipeptides in order to investigate their cerebroprotective properties. As a result of the study, 13 novel 6,7-dimetho-xyquinazolin-4(3H)-one derivatives were synthesized. Cerebral ischemia in rats was reproduced by irreversible right-sided occlusion of the middle cerebral artery using the Tamura method, and the area of brain necrosis was evaluated. Cognitive functions were evaluated in the Y-maze test. Among the studied quinazolinone derivatives, compounds 3i, 3j and 3k have the most pronounced cerebrotropic activity, which is not inferior to ethylmethylhydroxypyridine succinate in terms of pharmacological activity, making them promising objects for further research.

Synthesis, Biological Activitiy and DFT Study of New Azaphenalene Derivatives

In this study, synthesis, biological activitiy and DFT properties of azaphenalene derivatives will be investigated. Consequently, n-benzoyl-1,3 diaryl-2(para formyl) azaphenalene derivatives were synthesized via an irreversible unilateral condensation reaction of the aromatic dial, the 2,7-naphthalene diol, carboxylic acids, and NH3 (aq) (25%). An aliphatic and aromatic carboxylic acid and an aromatic dial were used in this multicomponent reaction, and good yields were obtained for the products. The method is quick and easy without solvents, and the reaction takes place in a short amount of time, this type of reaction is precessed by a Betti reaction. Pseudomonas and Staphylococcus saprophyticus were used as Gram-positive and Gram-negative bacteria susceptible to the antimicrobial activity of azaphenalene derivatives. The resulting antimicrobial activity was moderate to good. Comparing other synthesized compounds, compound 5j showed the strongest inhibition against Staphylococcus saprophyticus. Compounds 5c, 5f, 5e, and 5i also demonstrated good inhibition against Pseudomonas aeruginosa, while other synthesized compounds showed moderate inhibition. Analyses of the density functional theory (DFT) of azaphenalene derivatives in the gas phase were performed at the B3LYP/6-31G* level of theory and the results were compared with the experimental value. Calculations included thermodynamic parameters, electronic properties, frontier analysis, and molecular electrostatic potential (MEP). The DFT results agree with the experimental results, indicating that all azaphenalene derivatives are in stable vibrational states. A comparison of experimental and frontier analyses revealed a good agreement.

Synthesis, molecular docking, anti-cancer activity, and in-silico ADME analysis of novel spiroacenaphthylene pyrrolizidine derivatives

A short and efficient multicomponent sequence for synthesizing spiroacenaphthylene pyrrolizidine analogs 5a-svia 1,3-dipolar cycloaddition reaction of azomethine ylide with chalcones 4a-s without any catalyst. Synthesized compounds 5a-s were characterized by spectral data and single crystal X-ray diffraction study. In-vitro anti-proliferative activity of compounds 5a-s against K562-leukemia showed that compounds 5e, 5i, 5l, 5m and 5o have an IC50 value of 54.07, 47.48, 50.57, 53.85 and 49.57 µg/ml respectively and exhibited H-bonding with LYS 875 in the molecular docking studies against the 2J5F protein and showed favourable in-silico ADME properties. Compound 5o showed favourable in-vitro anti-proliferative activity against K562-leukemic cell line and favourable in-silico ADME properties. It can serve as a template to develop further as a lead molecule and act as a tyrosine kinase inhibitor.

Synthesis, antioxidant, and antimicrobial activity of some novel N‐substituted derivatives of 3‐(benzo[b]thiophen‐2‐yl)‐5‐(3‐[trifluoromethyl]styryl)‐4,5‐dihydro‐1H‐pyrazole

AbstractThe new series of various N‐substituted pyrazoline derivatives containing benzo[b]thiophene and styryl with trifluoromethyl substitution at meta‐ position were synthesized. Compound 1‐(3‐(benzo[b]thiophen‐2‐yl)‐5‐(3‐[trifluoromethyl]styryl)‐4,5‐dihydro‐1H‐pyrazol‐1‐yl)‐2‐chloroethan‐1‐one (3b) was further substituted with various thiols. The structures of newly synthesized compounds were characterized by UV, IR, NMR, and Mass and had been screened for antioxidant and antimicrobial activity. The in vitro antioxidant screening revealed that hydroxyl radical scavenging (HRS) activities of compounds 3a, 3b, 3c, 3f, 3i, 3j, 4a, and 4c are stronger than the other compounds and the in vitro antimicrobial activities of the compounds were tested against Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Bacillus subtilis, Staphylococcus aureus, Enterococcus faecalis, Aspergillus flavus, and Aspergillus Niger. The compounds 3d and 3e exhibit good activity against P. mirabilis. Compounds 3a, 3b, 3c, 3 h, 3i, 3j, and 4a showed significant activity against S. aureus. Compounds 3e and 3f showed very good activity against A. flavus. Compounds 3e, 3f, and 4c showed good activity against A. Niger.

Design, synthesis, biological evaluation, and in silico studies of 2-aminobenzothiazole derivatives as potent PI3Kα inhibitors.

A new series of 2-aminobenzothiazole derivatives was designed, synthesized and evaluated for their anticancer activity against the MCF7, MDAMB-231, and HepG2 cancer cell lines. All synthesized derivatives (8a-8n) demonstrated moderate to high anticancer activity against the tested cell lines. As the most potent compound in the series, compound 8i displayed excellent inhibitory potency with an IC50 value of 6.34 μM and compound 8m displayed an IC50 value of 8.30 µM against the MCF7 cell line compared to the standard drug HS-173 (IC50 = 10.25 μM). PI3K enzyme activity assays demonstrated that compound 8i is highly selective against PI3Kα, with an IC50 value of 1.03 nM. Wound healing assays and cell cycle analysis of compounds 8i and 8m revealed that both compounds suppressed the migration of MCF7 cells and induce cell cycle arrest in the S phase. In the cell death assay, compound 8i was revealed to induce apoptosis in a dose-dependent pattern; further Western blot assays revealed that compound 8i obviously decreases the levels of the antiapoptotic proteins Bcl-xL and Mcl-1. Downregulation of the expression of p-Akt confirmed the PI3K inhibitory activity of compound 8i. The molecular docking and molecular dynamicssimulation studies performed were found in agreement with the PI3Kα inhibitory activity assessments performed experimentally.

Synthesis, Structural Characterization, and Cytotoxic Activity of New Benzo[d]imidazo[2,1-b]thiazole Derivatives Against MCF-7 Breast Cancer Cells.

Breast cancer is an invasive disease with a high prevalence among females. Despite various treatments, studies are still ongoing to find an effective treatment for this disease. This study aimed to synthesize a new series of diaryl benzo[d]imidazo[2,1-b]thiazole compounds containing aminoethoxy side chain and in vitro investigate their cytotoxicity on a human breast cancer cell line (MCF-7). Twelve derivatives (6a-6l) were synthesized from this scaffold, the structures of which were spectroscopically confirmed. The cytotoxic effects of the derivatives on the MCF-7 cell line were also assessed using the MTT assay. All these compounds showed a good inhibitory effect on the MCF-7 cell line, compared to that of tamoxifen. Compounds (6i) and (6j) showed higher cytotoxicity with relevant inhibitory effects of 81% and 73%, respectively.

Novel indazole derivatives as potent apoptotic antiproliferative agents by multi-targeted mechanism: Synthesis and biological evaluation

Indazole is a significant class of heterocyclic compounds with a wide range of biological activity. We display here the synthesis and biological evaluation of a novel series of indazole derivatives 6a-v, which are differently substituted at the 6-position of the indazole moiety. The antiproliferative activity of compounds 6a-v was tested against four human cancer cell lines, using the MTT assay and doxorubicin as the reference drug. Compounds 6f, 6i, 6j, 6 s, and 6n were the most effective synthesized derivatives, with GI50 values of 0.77, 0.86, 1.05, 1.05, and 1.07 µM, respectively, against the 4 cell lines, in comparison to the control doxorubicin (GI50 = 1.10 µM). Compounds 6f, 6i, 6j, and 6 s the most potent derivatives as antiproliferative agents, displayed the utmost inhibitory activity against EGFR, and CDK2 and c-Met. Compounds 6f, 6n, and 6 s induced apoptosis through cytochrome C overexpression and activation of the intrinsic apoptotic pathway generated by the investigated compounds.

Design, synthesis, molecular docking and antimicrobial and antimycobacterial activities of novel hybrid of coumarin-cinnamic acids

• New fourteen coumarin-cinnamic hybrids synthesized. • Compounds tested against various bacterial, fungal, and mycobacterial strains. • Molecular docking was performed against DNA gyrase B of E. coli Protein. • 6g, 6i, and 6j showed significant antimicrobial and antimycobacterial activity. A series of novel hybrids containing coumarin-cinnamic acid derivatives (6a-6n) were designed and synthesized to screen their antimicrobial and antimycobacterial activities. The results indicated compounds 6i (MIC=50 µg/ml, E. coli and MIC=100 µg/ml, C. albicans ) and 6j (MIC=12.5 µg/ml, E. coli ) exhibited the most potent activity against bacterial and fungal strains amongst synthesized compounds. Compound 6g (MIC=50 µg/ml), 6i (MIC=25 µg/ml), and 6j (MIC=62.5 µg/ml) showed magnificent activity against Mycobacterium tuberculosis H 37 Rv. Designing of reported derivatives is impacted by molecular docking study and interaction with DNA GyrB of E. coli also proclaimed that compounds 6g (-9.0 kcal/mol), 6i (-8.5 kcal/mol), and 6j (-8.4 kcal/mol) is showing binding affinity and interaction from the synthesized fourteen compounds, comparing with experimental results. Compounds 6g, 6i, and 6j showed promising candidates for drug discovery with significant in vitro antimicrobial and antimycobacterial activities. Subject area Organic chemistry and Computational Chemistry Compounds 2-oxo-2 H -chromen-7-yl-3-(4-(4-substituted)phenyl)acrylate Data category Spectral, Biological and Computational data Data acquisition format IR, NMR, Mass spectra, Elemental analysis. Data type Analyzed. Procedure The co-crystal structure of DNA GyrB, PDB ID: 1KZN was downloaded from Protein Data Bank (PDB). The protein was prepared by deleting water molecules, adding missing hydrogens and Kollman charge. Data accessibility Data included in the article

Design, Synthesis and Cytotoxicity Evalufation of Substituted Benzimidazole Conjugated 1,3,4-Oxadiazoles.

Two series of 2-substituted benzimidazole conjugated 1,3,4-oxadiazole derivatives were designed, synthesized and evaluated for their cytotoxic activities against the three human cancer cell lines (cervical cancer (HeLa), breast cancer (MCF-7) and lung cancer (A549)). As the results 14 compounds demonstrated consistent to stronger cytotoxicities compared to the control 5-fluorouracil (5-FU) towards the tested cell lines including 4c (HeLa); 4b, 4e, 4h, 7i-j, 7m-n, 7s (MCF-7); 7b (MCF-7, A549); 7h (HeLa, MCF-7); and 4d, 4i, 7c (HeLa, MCF-7, A549), with the IC50 ranging from 2.7 to 38 µM. Notably, compound 4b illustrated almost 5-fold activity against the MCF-7 while 4d, 4i were 9- and 8-fold (HeLa), 4.5- and 13-fold (MCF-7), 4.7- and 4-fold (A549) increase in activity compared to 5-FU, respectively, and were found as lead compounds. These findings suggest that compounds 4b, 4d and 4i merit further characterization and can serve as promising scaffolds in the discovery of new potent anticancer agents.

4-Chlorophenyl-N-furfuryl-1,2,4-triazole Methylacetamides as Significant 15-Lipoxygenase Inhibitors: an Efficient Approach for Finding Lead Anti-inflammatory Compounds.

Lipoxygenases (LOXs) are a class of enzymes that catalyze the production of pro-inflammatory mediators, such as leukotrienes and lipoxins, via an arachidonic acid cascade as soon as they are released from the membrane phospholipids after tissue injury. In continuation of our efforts in search for new LOX inhibitors, a series of chlorophenyl-furfuryl-based 1,2,4-triazole derivatives were prepared and evaluated for their 15-LOX inhibitory activities. A simple precursor, 4-chlorobenzoic acid (a), was consecutively transformed into benzoate (1), hydrazide (2), semicarbazide (3), and N-furfuryl 5-(4-chlorobenzyl)-4H-1,2,4-triazole (4), which when further merged with electrophiles (6a–o) resulted in end products (7a–o). The structural elucidations of the newly synthesized compounds (7a–o) were carried out by Fourier transform infrared, 1H-, 13C NMR spectroscopy, EI-MS, and HR-EI-MS spectrometry. The inhibitive capability of compounds (7a–o) on soybean 15-LOX was performed in vitro using the chemiluminescence method. The compounds 7k, 7o, 7m, 7b, and 7i demonstrated potent activities (IC50 17.43 ± 0.38, 19.35 ± 0.71, 23.59 ± 0.68, 26.35 ± 0.62, and 27.53 ± 0.82 μM, respectively). These compounds revealed 79.5 to 98.8% cellular viability as measured by the MTT assay at 0.25 mM concentration. The structure-activity relationship (SAR) studies showed that the positions and the nature of substituents bonded to the phenyl ring are important in the determination of 15-LOX inhibitory activities. ADME, in silico, and density functional theory studies supported the evidence as yet another class of triazoles with potential lead properties in search for anti-LOX compounds with a safe gastrointestinal safety profile for various inflammatory diseases. Further work is in progress on the synthesis of more derivatives in search for anti-inflammatory agents.

Synthesis of new thienylnicotinamidines: Proapoptotic profile and cell cycle arrest of HepG2 cells.

Fourteen new thienylnicotinamidines and their analogs 5a-5k, 12, 13a, and 13b were prepared and their antiproliferative potential was evaluated against the growth of 60 cancer cell lines. The tested compounds had a strong antiproliferative efficacy against almost all cancer cell lines, with the average GI50 at ~2.20 µM. The effect of the thienylnicotinamidines on the growth of normal lung fibroblast cells (WI-38) indicated that these derivatives are safe to the normal cells. The selectivity index (SI) ranges from 5.5- to 42.0-fold. The conceivable mechanisms of action of the effective compounds 5d, 5f, 5g, 5i, 5j, and 5k with high SI were investigated. Although the thienylnicotinamidines are similar in structure, they could be divided into three groups as per their effects on gene expression: The first group (5d and 5f) elevated p53 and caspase 3 expression, the second group (5g and 5i) elevated p53 expression, and the last group (5j and 5k) elevated p53 and reduced topoII expression. Many thienylnicotinamides inhibited the vascular endothelial growth factor receptor-2 (VEGFR-2) in cell lysates at concentrations comparable to or better than pazopanib. The data of caspase 3 expression were confirmed by measuring the protein level by Western blot and the activity of the cleaved active enzyme. The ability to arrest the cell cycle and induce apoptosis was confirmed by flow cytometry. Taken together, two derivatives, 5d and 5f, with a distinctive VEGFR-2 inhibitory activity and a proapoptotic and cell cycle arrest profile merit further investigations.