Browsing by Author "Küçükgüzel, İlkay"

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Citation Count: 0
Bangladesh Journal of Pharmacology
(Bangladesh Pharmacological Soc, 2024) Küçükgüzel, İlkay; Guven, Cansu Tamniku; Duracik, Merve; Ozakpinar, Ozlem Bingol; Kucukguzel, Ilkay; Eczacılık Meslek Bilimleri Bölümü
[No Abstract Available]
Citation Count: 1
in Silico Design, Synthesis and Antitubercular Activity of Novel 2-Acylhydrazono as Enoyl-Acyl Carrier Protein Reductase Inhibitors
(Taylor & Francis inc, 2024) Küçükgüzel, İlkay; Kumari, Jyothi; Tamhaev, Rasoul; Mourey, Lionel; Lherbet, Christian; Sriram, Dharmarajan; Kucukguzel, Ilkay; Eczacılık Meslek Bilimleri Bölümü
Mycobacteria regulate the synthesis of mycolic acid through the fatty acid synthase system type 1 (FAS I) and the fatty acid synthase system type-2 (FAS-II). Because mammalian cells exclusively utilize the FAS-I enzyme system for fatty acid production, targeting the FAS-II enzyme system could serve as a specific approach for developing selective antimycobacterial drugs. Enoyl-acyl carrier protein reductase enzyme (MtInhA), part of the FAS-II enzyme system, contains the NADH cofactor in its active site and reduces the intermediate. Molecular docking studies were performed on an in-house database (similar to 2200 compounds). For this study, five different crystal structures of MtInhA (PDB Code: 4TZK, 4BQP, 4D0S, 4BGE, 4BII) were used due to rotamer difference, mutation and the presence of cofactors. Molecular dynamics simulations (250 ns) were performed for the novel 2-acylhydrazono-5-arylmethylene-4-thiazolidinones derivatives selected by molecular docking studies. Twenty-three compounds selected by in silico methods were synthesized. Antitubercular activity and MtInhA enzyme inhibition studies were performed for compounds whose structures were elucidated by IR,H-1-NMR,C-13-NMR, HSQC, HMBC, MS and elemental analysis. Communicated by Ramaswamy H. Sarma
Citation Count: 3
Novel Azole-Urea Hybrids as Vegfr-2 Inhibitors: Synthesis, In Vitro Antiproliferative Evaluation And In Silico Studies
(Elsevier, 2023) Küçükgüzel, İlkay; Kulabas, Necla; Erdogan, Omer; Cevik, Ozge; Dere, Damla; Yelekci, Kemal; Kucukguzel, Ilkay; Eczacılık Meslek Bilimleri Bölümü
The vascular endothelial growth factor receptor-2 (VEGFR-2) is a receptor tyrosine kinase known to be abnormally expressed in various malignant tumors, including breast cancer, and is considered one of the most important contributors to tumor angiogenesis. Sorafenib is one of many VEGFR-2 inhibitors that have received approval for clinical use from the US FDA in recent years. Accordingly, in this study, the synthesis of two new pyrazoles, six 1,3,4-oxadiazoles, four 1,3,4-thiadiazoles, and ten 1,2,4-triazole-3-thione derivatives having structural characteristics similar to sorafenib was carried out. A preliminary screening of synthesized compounds and known inhibitors sorafenib and staurosporine at 10 mu M concentration on in vitro activity of VEGFR-2 was performed, and compounds 10c, 8a, and 11 g were identified as the most potent derivatives with% VEGFR-2 residual activities lower than 30%, and dose-dependent inhibition studies was carried out to determine the IC50 values of these inhibitors. Compound 10c was found to be the most potent inhibitor of VEGFR-2 activity with an IC50 value of 0.664 mu M. The anti-proliferative activity of synthesized derivatives was assessed against a breast carcinoma (MCF-7) cell line, a triple negative human breast adenocarcinoma (MDA-MB-231) cell line, and noncancerous fibroblast cells (L929). Compound 8a displayed superior activity when compared to sorafenib against MCF-7 (7.69 fold) and MDA-MB-231 (1.52 fold) cell lines while displaying 3.75-fold less toxicity against the normal L929 cell line. Annexin V binding assay revealed that compound 8a significantly increased early and late apoptosis in MCF-7 cells and late apoptosis and necrosis in MDA-MB-231 cells. Computational studies such as molecular docking and ADMET evaluation were performed to elucidate the binding interactions and druglikeness of the synthesized compounds. The results indicate that compound 8a could be a promising candidate for the development of a novel anti-angiogenic and anti-proliferative agent.
Citation Count: 0
Synthesis and Anti-Hcv Activity of Novel 5-Arylmethylene Derivatives Via Suppression of Ns5b Polymerase and Cox-2
(Elsevier, 2024) Küçükgüzel, İlkay; Lee, Jin-Ching; Ozakpinar, Ozlem Bingol; Kucukguzel, Ilkay; Eczacılık Meslek Bilimleri Bölümü
Hepatitis C (HCV) is a viral infection that leads to forms of acute and chronic liver disease, including cirrhosis (scarring of the liver) and liver cancer. The World Health Organization (WHO) estimated in 2019 that approximately 290,000 people died from hepatitis C (mostly from cirrhosis and hepatocellular carcinoma). Directacting antiviral drugs (DAAs) can cure more than 95% of individuals with hepatitis C infection, while research on the discovery of new antiviral agents is still ongoing. The Hepatitis C virus (HCV) can cause various biochemical changes in liver cells, and some of these changes are associated with the COX-2 enzyme. The identification of its role in promoting growth in liver cells as well as its involvement in various cancer types, including hepatocellular carcinoma, has made COX-2 an important target in the development of new agents effective against HCV. In this study, thirty-six new 5-arylmethylene-2-imino-1,3-thiazolidin-4-one derivatives (5a-s, 6a-s) were synthesized through Knoevenagel condensation of 2-[(4-substitutedpyridin-2-yl)imino]-1,3thiazolidin-4-one derivatives with various aldehydes. Structures of the synthesized compounds were elucidated by the use of spectral and chromatographic techniques, besides elemental analyses. Four compounds were selected for further studies as they were found to suppress the NS5B protein with anti-HCV activity using the Western Blotting method. The selected compounds 5o, 6m, 6r, and 6s inhibited HCV with EC50 values of 8.0 +/- 0.2 mu M, 13.9 +/- 0.45, 9.2 +/- 0.2 mu M, and 12.1 +/- 0.1 mu M, respectively. It was determined that these compounds reduced HCV-induced COX-2 promoter activity in Ava5 cells compared to Huh7 cells. The antiviral effects of the compounds were also investigated on DENV, closely related to HCV due to sharing certain biological, structural, and mechanical properties throughout their life cycles. However, no significant effect was observed in the preliminary screening study, indicating the compounds' specificity for HCV. Considering the relationship between HCV, DENV, and COX-2, the compounds' COX-1 and COX-2 enzyme inhibition potentials were investigated both in vitro and in silico. Compounds 6d, 6e, 6f, and 6m, which exhibited high selective COX-2 inhibition, were discussed for their interactions with the active site. Our study revealed that our target compounds suppressed COX-2 both at the protein level and through enzyme inhibition, thus providing promising findings for the discovery of new anti-HCV effective COX-2 inhibitors.
Citation Count: 0
Synthesis of Novel Triazole-Urea Hybrids and Their Antiproliferative Activity Against Pancreatic Cancer Through Suppression of Eef2k and Induction of Apoptosis
(Elsevier, 2024) Küçükgüzel, İlkay; Ozdemir, Burcu; Cece, Onur; Armagan, Guliz; Erdogan, Mumin Alper; Erdogan, Omer; Kucukguzel, Ilkay; Eczacılık Meslek Bilimleri Bölümü
Pancreatic cancer is one of the deadliest cancers with its highly aggressive and metastatic character and there is a huge unmet need for new drugs treating pancreatic cancer. In the present study, a series of 1,2,4-triazole-urea conjugates have been designed and synthesized as novel candidates of antiproliferative agents against pancreatic cancer cells. Among them, compounds 33, 34, 35 and 38 possesing IC50 values between 0.231 and 0.488 mu M against PANC-1 cells demonstrated the highest anti-proliferative activity. These compounds presenting the highest antiproliferative activity were evaluated for further biological studies. The same four compounds inhibited colony formation in pancreatic cancer cells dose dependently. Western blot study on the selected compounds showed that compounds 33 and 38 significantly reduced eEF2K protein levels in cancer cells. These compounds displayed an effective eEF2K activity suppression by down-regulated levels of unphosphorylated eEF2 in PANC-1 cells. Compounds 33, 34, 35 and 38 were also demonstrated to induce apoptosis and activate caspase 3/7. In silico studies were performed to predict the druggability and ADMET/ properties of the active molecules. In summary, 1,2,4-triazole-urea conjugates developed in this study represent a novel and promising lead structure with anticancer activity against pancreatic cancer achieved through eEF2K activity suppression. Compounds being referred to are the first "triazole-urea hybrid" molecules found to be effective against pancreatic cancer.