New benzimidazole-oxadiazole derivatives as potent VEGFR-2 inhibitors: Synthesis, anticancer evaluation, and docking study.

We report herein, the design and synthesis of benzimidazole-oxadiazole derivatives as new inhibitors for vascular endothelial growth factor receptor-2 (VEGFR-2). The designed members were assessed for their in vitro anticancer activity against three cancer cell lines and two normal cell lines; A549, MCF-7, PANC-1, hTERT-HPNE and CCD-19Lu. Compounds 4c and 4d were found to be the most effective compounds against three cancer cell lines. Compounds 4c and 4d were then tested for their in vitro VEGFR-2 inhibitory activity, safety profiles, and selectivity indices using the normal hTERT-HPNE and CCD-19Lu cell lines. It was determined that compound 4c was the most effective and safe member of the produced chemical family. Vascular endothelial growth factor A (VEGFA) immunolocalizations of compounds 4c and 4d were evaluated relative to control by VEGFA immunofluorescence staining. Compounds 4c and 4d inhibited VEGFR-2 enzyme with half-maximal inhibitory concentration values of 0.475 ± 0.021 and 0.618 ± 0.028 µM, respectively. Molecular docking of the target compounds was carried out in the active site of VEGFR-2 (Protein Data Bank: 4ASD).

Peripheral blood mononuclear cell microRNAs in coronary artery disease.

The accuracy of risk prediction for coronary artery disease can be improved with the use of novel molecular or genetic biomarkers. In this study, we investigated the difference of five selected microRNAs (miR or miRNA) in patients with coronary artery disease (CAD) and controls, assessed by coronary angiography. The study population consisted of 85 subjects, aged between 18 and 75 years and underwent invasive coronary angiography. Subjects with more than 30% stenosis in at least one coronary artery, patients with a history of prior percutaneous coronary intervention or coronary by-pass surgery were allocated to the patient group; whereas the subjects without at least 30% stenosis consisted the control group. Groups were similar in age, presence of hypertension, and smoking status. However, the proportion of males and subjects taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, beta blockers, nitrates, and statins were higher in the patient group. miR-221 and miR-155 were downregulated (P = .02 and .001, respectively), while miR-21 levels were significantly increased (P = .003) in the patient group compared to controls. Changes in miR-145 and miR-126 did not reach statistical significance (P > .05). miRNA- 21, miR-155, and miR-221 were differentially expressed between the patients and controls. miRNAs are promising biomarkers for CAD diagnosis, however, this requires further research with larger groups.

Imidazole-Derived Alkyl and Aryl Ethers: Synthesis, Characterization, In Vitro Anticancer and Antioxidant Activities, Carbonic Anhydrase I-II Inhibition Properties, and In Silico Studies.

Imidazole derivatives display extensive applications in pharmaceutical chemistry and have been investigated as bioactive compounds for medicinal chemistry. In this study, besides the starting materials (3a-c and 4a-c), synthesis, characterization, and biological activity studies were conducted on a total of 18 compounds, nine of which are known and the other nine are original. The compounds investigated in the study are a series of alkyl (7-15) and aryl (16-24) ether derivatives bearing substituted phenyl and imidazole rings, which were characterized using various methods including 1H NMR, 13C NMR, FT-IR analysis, elemental analysis, and mass spectroscopy. Computer-aided drug design studies have been carried out to predict the biological activities of compounds. Besides DFT calculations, the binding affinities of the compounds to EGFR, VEGFR2, FGFR1, HSP90, hCA I, and hCA II were investigated. Additionally, drug-likeness and ADME analyses were performed on the compounds. Anticancer, antioxidant, and enzyme inhibition activity tests were performed in biological activity studies on the synthesized compounds. Among the synthesized compounds, compounds 17 and 19-24 generally exhibited inhibition profiles against the widespread cytosolic hCA I isozyme with IC50 values ranging from 4.13 to 15.67 nM and cytosolic hCA II isozyme with IC50 values ranging from 5.65 to 14.84 nM. L929 (mouse fibroblast cell line) was used as the control healthy cell line, and MCF7 (breast cancer), C6 (rat glioblastoma), and HT-29 (colon cancer) cells were used in cell culture studies as cancer cell lines. Before the study on cancer cells, all compounds were examined on healthy cells, and their cytotoxicity was determined. As a result of these data, studies continued with six compounds determined to be nontoxic. On cancerous cells, it was determined that compounds 3a, 3b, 4a, 4b, 4c, and 7 had cytotoxic effects on both colon cancer and brain tumors. It was found that compound 3b had a more toxic effect than cisplatin on the glioma cell line with an IC50 value of 10.721 ± 0.38 µM, and compound 3a had a more toxic effect on the colon cancer cell line with an IC50 value of 20.88 ± 1.02 µM. However, it was determined that the same compounds did not have a statistically significant effect on breast cancer. Flow cytometry studies also showed that when the IC50 dose of compound 3b was applied to the C6 cell line, the cells tended to early and late apoptosis. Additionally, it has been shown by flow cytometry that the cell cycle stops in the G0/G1 phase. A similar effect was observed in the colon cancer cell line with compound 3a. Compound 3b caused early and late apoptosis of the colon cancer cell line with the applied IC50 dose and stopped the cell cycle in the G0/G1 phase. Finally, the FRAP method studied all synthesized compounds' antioxidant effects. According to the measured antioxidant power results, it was determined that no compound had a more effective reducing power than vitamin E.

Design, synthesis, and molecular docking studies of benzimidazole-1,3,4-triazole hybrids as carbonic anhydrase I and II inhibitors.

In this study, with an aim to develop novel heterocyclic hybrids as potent enzyme inhibitors, we synthesized a series of 10 novel 2-(4-(4-ethyl-5-(2-(substitutedphenyl)-2-oxo-ethylthio)-4H-1,2,4-triazol-3-yl)-phenyl)-5,6-dimethyl-1H-benzimidazole (5a-5j) derivatives and characterized by 1 H-NMR, 13 C-NMR, and HRMS. These compounds were evaluated for their inhibitory activity against hCA I and hCA II. All the compounds exhibited good hCA I and hCA II inhibitory activities with IC50 values in range of 1.288 µM-3.122 µM. Among all these compounds, compound 5e, with an IC50 value of 1.288 µM is the most active against carbonic hCA I. Compound 5h with an IC50 value of 1.532 µM is the most active against carbonic hCA-II. Compounds 5a-5j were also evaluated for their cytotoxic effects on the L929 mouse fibroblast (normal) cell line. The compounds were also analyzed for their antioxidant capacity by TAS, FRAP, and DPPH activity. Enzyme inhibition kinetics showed all compounds 5a-5j to inhibit the enzyme by non-competitive. The most active compound 5e for hCA I and compound 5h for hCA-II were subjected to molecular docking, which revealed their binding interactions with the enzyme's active site, confirming the experimental findings.

Synthesis, DFT Calculations, In Silico Studies, and Antimicrobial Evaluation of Benzimidazole-Thiadiazole Derivatives.

In this study, a series of new benzimidazole-thiadiazole hybrids were synthesized, and the synthesized compounds were screened for their antimicrobial activities against eight species of pathogenic bacteria and three fungal species. Azithromycin, voriconazole, and fluconazole were used as reference drugs in the mtt assay. Among them, compounds 5f and 5h showed potent antifungal activity against C. albicans with a MIC of 3.90 µg/mL. Further, the results of the antimicrobial assay for compounds 5a, 5b, 5f, and 5h proved to be potent against E. faecalis (ATCC 2942) on the basis of an acceptable MIC value of 3.90 µg/mL. The cytotoxic effects of compounds that are effective as a result of their antimicrobial activity on healthy mouse fibroblast cells (L929) were evaluated. According to HOMO-LUMO analysis, compound 5h (with the lower ΔE = 3.417 eV) is chemically more reactive than the other molecules, which is compatible with the highest antibacterial and antifungal activity results. A molecular docking study was performed to understand their binding modes within the sterol 14-α demethylase active site and to interpret their promising fungal inhibitory activities. Molecular dynamics (MD) simulations of the most potent compounds 5f and 5h were found to be quite stable in the active site of the 14-α demethylase (5TZ1) protein.

Synthesis of Benzimidazole-1,2,4-triazole Derivatives as Potential Antifungal Agents Targeting 14α-Demethylase.

Invasive fungal infections (IFIs) are increasing as major infectious diseases around the world, and the limited efficacy of existing medications has resulted in substantial morbidity and death in patients due to the lack of effective antifungal agents and serious drug resistance. In this study, a series of benzimidazole-1,2,4-triazole derivatives (6a-6l) were synthesized and characterized by 1H NMR, 13C NMR, and HR-MS spectral analysis. All the target compounds were screened for their in vitro antifungal activity against four fungal strains, namely, C. albicans, C. glabrata, C. krusei, and C. parapsilopsis. The synthesized compounds exhibited significant antifungal potential, especially against C. glabrata. Three compounds (6b, 6i, and 6j) showed higher antifungal activity with their MIC values (0.97 µg/mL) compared with voriconazole and fluconazole. Molecular docking provided a possible binding mode of compounds 6b, 6i, and 6j in the 14α-demethylase active site. Our studies suggested that the benzimidazole-1,2,4-triazole derivatives can be used as a new fungicidal lead targeting 14α-demethylase for further structural optimization. In addition, their effects on the L929 cell line were also investigated to evaluate the cytotoxic effects of the compounds. SEM analyses were performed to examine the effects of compounds 6a, 6i, and 6j on C. glabrata cells under in vivo experimental conditions.

Correction: Evaluation of the effects of newly synthesized metallophthalocyanines on breast cancer cell lines with photodynamic therapy.

Correction for 'Evaluation of the effects of newly synthesized metallophthalocyanines on breast cancer cell lines with photodynamic therapy' by Hayrani Eren Bostanci et al., Dalton Trans., 2022, 51, 15996-16008, https://doi.org/10.1039/d2dt01912d.

Synthesis and Molecular Docking of New N-Acyl Hydrazones- Benzimidazole as hCA I and II Inhibitors.

BACKGROUND: The carbonic anhydrases (CAs) which are found in most living organisms is a member of the zinc-containing metalloenzyme family. The abnormal levels and activities are frequently associated with various diseases therefore CAs have become an attractive target for the design of inhibitors or activators that can be used in the treatment of those diseases. METHODS: Herein, we have designed and synthesized new benzimidazole-hydrazone derivatives to investigate the effects of these synthesized compounds on CA isoenzymes. Chemical structures of synthesized compounds were confirmed by 1H NMR, 13C NMR, and HRMS. The synthetic derivatives were screened for their inhibitory potential against carbonic anhydrase I and II by in vitro assay. RESULTS: These compounds have IC50 values of 5.156-1.684 µM (hCA I) and 4.334-2.188 µM (hCA II). Inhibition types and Ki values of the compounds were determined. The Ki values of the compounds were 5.44 ± 0.14 µM-0.299 ± 0.01 µM (hCA I) and 3.699 ± 0.041 µM-1.507 ± 0.01 µM (hCA II). The synthetic compounds displayed inhibitory action comparable to that of the clinically utilized reference substance, acetazolamide. According to this, compound 3p was the most effective molecule with an IC50 value of 1.684 µM. Accordingly, the type of inhibition was noncompetitive and the Ki value was 0.299 ± 0.01 µM. CONCLUSION: According to the in vitro test results, detailed protein-ligand interactions of the compound 3p, which is more active against hCA I than standard azithromycin (AZM), were analyzed. In addition, the cytotoxic effects of the compounds on the L929 healthy cell line were evaluated.

Evaluation of the effects of newly synthesized metallophthalocyanines on breast cancer cell lines with photodynamic therapy.

In this study, the new phthalonitrile derivative 3-(4-(3-oxobutyl)phenoxy)phthalonitrile (1) and its non-peripheral metallophthalocyanine derivatives [zinc (2), copper (3), cobalt (4), manganese (5), gallium (6), and indium (7)] were synthesized. The newly synthesized phthalocyanines were characterized by standard spectroscopic methods, such as FT-IR, 1H NMR, UV-Vis, fluorescence spectroscopies, and MALDI-TOF spectrometry. Aggregation behaviors of the novel phthalocyanines were investigated by UV-Vis spectroscopy. The effect of pH change on the electronic and emission spectra of the newly synthesized phthalocyanine derivatives was studied in THF media. The electronic spectra of the new zinc (2), copper (3), and cobalt (4) phthalocyanines exhibited bathochromic shifts in acidic pH values due to the presence of monoprotonated forms. Surprisingly, the same effect was not observed for manganese (5) and indium (7) phthalocyanines. On the other hand, gallium (6) showed a slight red-shifted band with the addition of HCl to the medium. Also, it was determined that the synthesized zinc (2) and gallium (6) phthalocyanines had a selective phototoxic effect on the MCF-7 breast cancer cell line compared to the MCF-10A healthy breast cell line. The IC50 values of zinc (2) and gallium (6) phthalocyanines were determined for MCF-7 and MCF-10A cell lines. The IC50 values of MCF-7 for compounds 2 and 6 were found to be 1.721 ± 0.4 µg mL-1 and 7.406 ± 0.32 µg mL-1, respectively. The IC50 values of MCF-10A for phthalocyanines 2 and 6 were found to be 48.90 ± 0.69 µg mL-1 and 14.77 ± 1.09 µg mL-1, respectively. In the LDH (lactate dehydrogenase)-ELISA study, the LDH levels that formed on a cellular basis after the application were measured, and it was observed that the cells were directed towards apoptosis. In addition, it was observed that cancer cells underwent more apoptosis than healthy cells as a result of this application with cell-cycle and dead cell kits performed by flow cytometry. This research shows that non-peripheral substituted gallium and zinc phthalocyanine derivatives (2 and 6) can be suitable photosensitizers for the photodynamic treatment of breast cancers.

Synthesis, Molecular Docking, Dynamics, Quantum-Chemical Computation, and Antimicrobial Activity Studies of Some New Benzimidazole-Thiadiazole Hybrids.

In this study, some new compounds, which are 2-aminothiadiazole derivatives linked by a phenyl bridge to the 2-position of the benzimidazole ring, were designed and synthesized as antimicrobial agents. The structures of the compounds were elucidated by 1H and 13C NMR spectroscopy, high-resolution mass spectrometry, and elemental analysis. The antifungal activities of the synthesized compounds were tested on Candida albicans, Candida krusei, Candida glabrata, and Candida parapsilosis. Compound 5f is more active against C. albicans and C. glabrata than standard fluconazole and varicanazole. Compounds were also evaluated for their counteracting activity against Gram-positive Escherichia coli, Serratia marcescens, Klebsiella pneumoniae, and Pseudomonas aeruginosa and Gram-negative Enterococcus faecalis, Bacillus subtilis, and Staphylococcus aureus. Compounds 5c and 5h had minimum inhibitory concentrations against E. faecalis close to that of the standard azithromycin. Molecular docking studies were performed against Candida species' 14-α demethylase enzyme. 5f was the most active compound against Candida species, which gave the highest docking interaction energy. The stabilities of compounds 5c and 5f with CYP51 were tested using 100 ns molecular dynamics simulations. According to the theoretical ADME calculations, the profiles of the compounds are suitable in terms of limiting rules. HOMO-LUMO analysis showed that 5h is chemically more reactive (represented with the lower ΔE = 3.432 eV) than the other molecules, which is compatible with the highest antibacterial activity result.

Increased urinary 6-hydroxymelatoninsulfate levels in attention deficit hyperactivity disorder diagnosed children and adolescent.

There are some studies in attention deficit hyperactivity disorder (ADHD) which note altered circadian rhythms, suggesting abnormalities in melatonin physiology. In order to better characterize the possible melatonin alteration in ADHD, in this study we aimed to detect daytime, nighttime and 24 h levels of 6-hydroxymelatoninsulfate (6-OH MS) in the patients diagnosed with ADHD. Twenty-seven patients between 6 and 16 years-old, who had been diagnosed initially with ADHD, but without other physical and psychiatric disease history and who had not taken psychotropic pharmacotherapy for six months, plus 28 healthy volunteer controls, were included in the study. Urine samples were collected during the whole 24 h cycle, daytime and nighttime separately to assess the time-dependent excretion of the 6-OH MS, which is the main urine metabolite of melatonin. The Enzyme-Linked Immunosorbent Assay (ELISA) method was used for measuring the urine 6-OH MS level. Daytime (15.4 (8.9-24.8) ng/ml vs 6.9 (2.5-15.9) ng/ml, p=0.002), nighttime (102.9 (65.3-197.7) ng/ml vs 61.5 (37.2-114.4) ng/ml, p=0.012) and 24 h (54.1 (34.6-83.9) ng/ml vs 27.3 (14.3-48.9) ng/ml, p=0.000) 6-OH MS levels median (25p-75p) were found to be significantly higher in the ADHD group. After adjustment for age and sex, there was a statistically significant difference between the ADHD group (59.8 ± 4.9) and control group (33.8 ± 4.8) in 24-h 6-OH MS levels (F(1, 51)=13.673, p=.001, partial η2=.211). There was no relationship between 6-OH MS levels and Conners Parent Rating Scale short form subscale scores for the ADHD group. These findings indicate that melatonin production is increased in ADHD cases. Further research is needed to determine and thereby understand the mechanisms underlying the higher melatonin production, to assess the impact of altered melatonin on the pathophysiology of ADHD.