Browsing by Author "Akbaba, Yusuf"

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Antikanser ve Antibakteriyel Aktiviteye Sahip Yeni Üre Türevi Bileşiklerin Sentezi, Biyokimyasal Karakterizasyonu ve Terapötik Uygulamaları
(2024) Kadı, Abdurrahim; Arslan, Mehmet Enes; Akbaba, Yusuf
Kanser günümüzde ölüm sebeplerinin en başında gelmektedir. Günümüzde glioblastoma ve nöroblastoma kanserine yakalanan hastalın her yüz binde yaklaşık üçü hayatını kaybetmektedir. Kanser tedavisinde kullanılan ilaçlar genellikle kemoterapi ilacı olup bir yandan hastaları tedavi ederken diğer yandan da hastaların sağlıklı dokularına ve bağışıklık sistemlerine zarar vererek kişilerin bakteriyel hastalıklara yakalanma ihtimallerini arttırmaktadır ve hastalara bu nedenle antibiyotik tedavileri de uygulanmaktadır. Yaptığımız bu çalışmada fenetilamin bazlı yeni üre türevleri sentezlenmiş olup, bu moleküllerin sitotoksik, genotoksik, antikanser ve antimikrobiyal etkileri araştırılmıştır. Sitotoksisite ve antikanser çalışmalarında MTT testi kullanılarak hücre canlılığı belirlenmiştir. Genotoksisite çalışmaların Hoechst 33258 floresan boyasıyla çekirdek yapı analizi yapılmıştır. Antimikrobiyal aktivite çalışmaları ise agar kuyucuk difüzyon ve mikrodilüsyon metotları kullanılarak yapılmıştır. Yapılan çalışmalar sonunda elde edilen veriler, bu çalışma ile ilk defa sentezlenmiş olan fenetilamin bazlı üre türevlerinin ilaçların sitotoksik ve genotoksik etki göstermediği ayrıca antikanser ve antimikrobiyal etki gösterdiği belirlenmiştir.
Carbonic Anhydrase Inhibitory Properties of Novel Benzylsulfamides Using Molecular Modeling and Experimental Studies
(Academic Press Inc Elsevier Science, 2014) Goksu, Suleyman; Naderi, Ali; Akbaba, Yusuf; Kalin, Pinar; Akincioglu, Akin; Gulcin, Ilhami; Salmas, Ramin Ekhteiari
In this study, a series of sulfamoyl carbamates and sulfamide derivatives were synthesized. Six commercially available benzyl amines and BnOH were reacted with chlorosulfonyl isocyanate (CSI) to give sulfamoyl carbamates. Pd-C catalyzed hydrogenolysis reactions of carbamates afforded sulfamides. The inhibition effects of novel benzylsulfamides on the carbonic anhydrase I, and II isoenzymes (CA I, and CA II) purified from fresh human blood red cells were determined by Sepharose-4B-L-Tyrosine-sulfanilamide affinity chromatography. In vitro studies were shown that all of novel synthesized benzylsulfamide analogs inhibited, concentration dependently, both hCA isoenzyme activities. The novel benzylsulfamide compounds investigated here exhibited nanomolar inhibition constants against the two isoenzymes. K-i values were in the range of 28.48 +/- 0.01-837.09 +/- 0.19 nM and 112.01 +/- 0.01-268.01 +/- 0.22 nM for hCAI and hCA II isoenzymes, respectively. Molecular modeling approaches were also applied for studied compounds. (C) 2014 Elsevier Inc. All rights reserved.
Computational Identification of Potential Antiviral Agents Against Monkeypox Virus
(2025) Aydemir, Dr. Murat; Hacimuftuoglu, Ahmet; Arslan, Mehmet Enes; Turkez, Hasan; Akbaba, Yusuf; Selvitopi, Harun; Selvitopi, Zulkuf
This study introduces a drug repurposing approach for monkeypox virus using molecular docking and molecular dynamics (MD) simulations to screen clinically approved drugs for other diseases. Potential candidates were analyzed with AutoDock software in two categories: (1) DNA polymerase inhibitors and (2) RNA polymerase inhibitors. Docking analysis identified seven promising compounds—five DNA polymerase and two RNA polymerase inhibitors—showing strong affinity toward monkeypox targets. MD simulations further confirmed their binding stability. Among them, etravirine (−8.04 kcal/mol) and valaciclovir (−7.57 kcal/mol) exhibited the highest affinity to DNA polymerase active sites at residues ASP347 and ASP462. Moreover, emetine dihydrochloride (−7.17 kcal/mol) demonstrated the strongest binding to the catalytic site of RNA polymerase. Consequently, etravirine and emetine dihydrochloride are proposed as potential therapeutics against monkeypox. Since these compounds are already approved by the U.S. Food and Drug Administration (FDA) for other viral infections, extensive safety testing and high development costs can be avoided, making this repurposing strategy an efficient and cost-effective option for managing monkeypox infection.
Design, Synthesis, Biological Evaluation, and in Silico Study of Novel Urea Derivatives as Inhibitors of Carbonic Anhydrase and Acetylcholine Esterase
(Univ Babes-Bolyai, 2022) Akbaba, Yusuf; Kalin, Ramazan
This study aimed to synthesize novel unsymmetrical urea derivatives containing biologically active tryptamine and phenethylamines and investigate their inhibition effects on human carbonic anhydrase (hCA) I and II isozymes as well as acetylcholinesterase (AChE). For this purpose, five different N,N'-dialkyl urea derivatives 18-22 were synthesized from tryptamine and substituted 2-phenethylamine. According to the results of inhibition, all of the synthesized urea derivatives effectively inhibited both hCA (I - II) and AChE enzymes at micromolar concentrations. The IC50 values for these molecules were determined to be in the range of 1.214-2.281 mu M for hCA-I, 0.888-2.984 mu M for hCA-II, and 0.309-0.816 mu M for AChE. The most potent inhibitors against hCA-I and hCA-II isozymes are compound 18 (IC50: 1.214 mu M; Ki: 0.984 +/- 0.277 mu M) and compound 19 (IC50: 0.888 mu M, Ki: 0.564 +/- 0.019 mu M), respectively. Furthermore, compound 20 (IC50: 0.309 M and Ki: 0.470 +/- 0.039 M) is the most effective AChE inhibitor. Molecular docking studies of compounds with the most effective inhibition were performed. The estimated binding energy values for compounds 18, 19, and 20 were calculated to be -7.81, -7.34, and -8.20 kcal/mol, respectively. Finally, the ADME studies were determined these compounds' physicochemical and pharmacokinetic descriptors and drug-like properties.
An Insight Into the Asymmetric Resolution of 1-Aminoindane Derivatives
(Wiley-V C H Verlag GmbH, 2023) Akincioglu, Akin; Akbaba, Yusuf; Kose, Leyla Polat; Goksu, Suleyman
Compounds with 1-aminoindane motif exhibit vital biological activities in the central nervous system. Therefore, it is very important to synthesize new compounds with this moiety and to obtain them in high enantiopurity. In this study, novel substituted 1-aminoindane derivatives were synthesized, and their asymmetric resolutions were carried out. Accordingly, the reduction of 1-indanones with NaBH4, conversion of alcohols to azides via an alternative Mitsunobu reaction followed by reduction of azides afforded (+/-)-1-aminoindane hydrochloride or hydrobromide salts. Amine salts were converted into their free amines by using excess amount of Et3N and then in situ occurred free (+/-)-amines were reacted with (R)-O-acetylmandeloyl chloride to give diastereomeric mixtures. The crystallization of the diastereomeric mixtures followed by hydrolysis yielded the corresponding asymmetric amines with high enantio-purity.
Novel Tetrahydronaphthalen-1 Ureas: Synthesis and Dual Antibacterial-Anticancer Activities
(Taylor & Francis Ltd, 2024) Akbaba, Yusuf; Kaci, Fatma Necmiye; Arslan, Mehmet Enes; Goksu, Suleyman; Mardinoglu, Adil; Turkez, Hasan
Cancer and antibiotic-resistant bacterial infections are significant global health challenges. The resistance developed in cancer treatments intensifies therapeutic difficulties. In addressing these challenges, this study synthesised a series of N,N '-dialkyl urea derivatives containing methoxy substituents on phenethylamines. Using isocyanate for the efficient synthesis yielded target products 14-18 in 73-76% returns. Subsequently, their antibacterial and anticancer potentials were assessed. Cytotoxicity tests on cancer cell lines, bacterial strains, and a healthy fibroblast line revealed promising outcomes. All derivatives demonstrated robust antibacterial activity, with MIC values ranging from 0.97 to 15.82 mu M. Notably, compounds 14 and 16 were particularly effective against the HeLa cell line, while compounds 14, 15, and 17 showed significant activity against the SH-SY5Y cell line. Importantly, these compounds had reduced toxicity to healthy fibroblast cells than to cancer cells, suggesting their potential as dual-functioning agents targeting both cancer and bacterial infections.
Potansiyel Biyolojik Aktif Bazı Asimetrik Feniletil Üre Türevlerinin Sentezi
(2021) Akbaba, Yusuf
Bu çalışmada, bir dizi potansiyel biyolojik aktif asimetrik üre türevi sentezlenmiştir. Buna göre (R)-(+)-1-feniletilamin (7) 1,1’-karbonildiimidazol ile su içerisinde reaksiyona sokulmuş ve imidazolid ara ürünleri oluşturulmuştur. Daha sonra üzerine fenetilamin (8a) ve sübstitüe fenetilamin türevleri (8b-e) verildi. Sonuç olarak, potansiyel biyolojik aktif yeni asimetrik üreler (R)-1-fenetil-3- (1-feniletil) üre (9a) ve sübstitüe türevleri (9b-e), % 60 - % 71 arasındaki verimlerle elde edildi.
A Straightforward Synthesis of Potentially Biologically Active Novel Urea Derivatives from 1,2,3,4-Tetrahydronaphthalene Acids
(Springer Wien, 2022) Akbaba, Yusuf
Potentially biologically active urea derivatives have been prepared in an efficient one-pot procedure from 1,2,3,4-tetrahydronaphthalene-2-carboxylic acids and characterized via several spectroscopy techniques. Ideal reaction times and temperatures, as well as the absence of metal catalysts and time-consuming and expensive purification chromatographic conditions, allowed the products to be in good yield. The obtained unsymmetrical urea derivatives in an economical and efficient synthetic methodology would be of great interest to be used for potential applications related to drug design, pharmaceutical, and medicinal chemistry. [GRAPHICS]
Substituted Tetrahydronaphthalen-1 Ureas: Synthesis, Characterization, and Biological Evaluations
(Wiley-V CH Verlag GmbH, 2022) Akbaba, Yusuf; Kaci, Fatma Necmiye; Goksu, Suleyman
Multi-target drug discovery is one of the most important objectives in the treatment of carcinogenesis because of the different outcomes of the disease such as bacterial infections due to impaired immune systems. Therefore, a series of new urea derivatives were synthesized to acquire both anti-proliferative and antimicrobial properties that can be used in chemotherapy. The anti-cancer and anti-microbial properties of synthesized urea compounds were investigated on the HeLa cancer line and multiple bacterial strains via using WST-8 and disc diffusion methods. In anticancer investigations against the HeLa cell line, one synthesized urea derivative exhibited the best activity (IC50: 58.9 mu M), which showed up to 8 times less toxic effect (SI: 8.5) against the non-cancerous human dermal fibroblast (PCS201-012) cell line. Additionally, some urea derivatives showed antibacterial activities against Acinetobacter baumannii, Escherichia coli, Enterococcus faecalis, and Staphylococcus aureus MRSA with the lowest MIC values. The MIC value obtained against Pseudomonas aeruginosa was at the level of mu M for all urea derivatives and was calculated as 7.8125 mu M. As a result, some synthesized urea derivatives may be considered as multipotent drug formulations with antibacterial and anticancer properties.
Synthesis and Anticancer Activity of Novel Ureas and Sulfamides Incorporating 1-Aminotetralins
(Elsevier Science Inc, 2017) Ozgeris, Bunyamin; Akbaba, Yusuf; Ozdemir, Ozlem; Turkez, Hasan; Goksu, Suleyman
Background and Aims. In the present study, a series of ureas and sulfamides derived from 1-aminotetralins were synthesized. For this purpose, urea and sulfamide analogues were synthesized from the reactions of substituted 1-aminotetralins with N,N-dimethylcarbamoyl chloride and N,N-dimethylsulfamoyl chloride. The anticancer activity of newly synthesized compounds was tested against human U-87MG glioblastoma and PC-3 prostate cancer cell lines. Cytotoxicity was examined using MTT and LDH release assays. Results. The obtained data revealed that tested compounds showed a variable degree of cytotoxic activity against the tested cell lines. 3-(5-methoxy-1,2,3,4-tetrahydronaphthalenl-y1)-1,1-dimethylurea (9) and 3-(6-methoxy-1,2,3,4-tetrahydronaphthalen-l-y1)-1, 1-dimethylurea (10) proved to be the most active cytotoxic members in this study. Conclusions. These two compounds could be considered as possible anticancer agents. (C) 2017 IMSS. Published by Elsevier Inc.
Synthesis and Asymmetric Resolution of a Dopaminergic Compound: 2-Amino
(Pergamon-Elsevier Science Ltd, 2016) Akbaba, Yusuf; Goksu, Suleyman; Sahin, Ertan; Kilic, Hamdullah; Secen, Hasan
The racemic synthesis and subsequent resolution of 2-amino-5-methoxyindane enantiomers were achieved starting from 5-bromoindan-2-ol in six steps with 38% total yield. The first step involved the substitution of the Br atom by using NaOMe in the presence of CuI to afford 5-methoxyindan-2-ol. The OH group of 5-methoxyindan-2-ol was converted into its mesylate ester, which was converted into the corresponding azide by reaction with sodium azide. The Pd C-catalyzed hydrogenation of the azide functional group in the presence of CHCI3, followed by neutralization of the amine hydrochloride salt with NaOH, furnished the rac-2-amino-5-methoxyindane. Next, rac-2-amino-5-methoxyindane was converted into its diastereomeric amide derivatives by reaction with (R)-mandeloyl chloride. The diastereomeric amide mixture was separated by recrystallization to give the (R,S)- and (R,R)-diastereomers. The absolute configuration of the (R,S)-isomer was determined by X-ray crystallography. The hydrolysis of these diastereomers gave (R)- and (S)-2-amino-5-methoxyindane with high enantiopurity. (C) 2016 Elsevier Ltd. All rights reserved.
Synthesis and Asymmetric Resolution of Substituted 2-Aminoindane and 2-Aminotetralin Derivatives
(Pergamon-Elsevier Science Ltd, 2023) Akincioglu, Akin; Akbaba, Yusuf; Kose, Leyla Polat; Akyuz, Leyla Demirkol; Goksu, Sueleyman
We performed the racemic synthesis and asymmetric resolution of one 2-aminoindane and three 2-aminotertalins due to their crucial biological roles in the central nervous system (CNS). For this reason, desired (+/-)-2-aminoindane and (+/-)-2-aminotetralin derivatives were synthesized starting from appropriate reagents. While highly enantio pure (+)-39, (+)-40, and ( inverted exclamation )-40 were obtained from the reaction of racemic amines with (R)-O-acetylmandeloyl chloride followed by crystallization, hydrolysis with KOH and acidification with HCl, (S)-42 and (-)-43 were synthesized via the reaction of racemic amines with (S)-mandelic acid and hydrolysis.(c) 2023 Elsevier Ltd. All rights reserved.
Synthesis and Carbonic Anhydrase Inhibitory Effects of Novel Sulfamides Derived from 1-Aminoindanes and Anilines
(Wiley-V C H Verlag Gmbh, 2014) Akbaba, Yusuf; Bastem, Enes; Topal, Fevzi; Gulcin, Ilhami; Maras, Ahmet; Goksu, Suleyman
Three 1-aminoindanes, four anilines and BnOH or t-BuOH were reacted with chlorosulfonyl isocyanate to give sulfamoyl carbamates. Pd-C catalysed hydrogenolysis reactions of carbamates or deprotection of the Boc group of the carbamates with CF3CO2H afforded seven novel sulfamides. Human carbonic anhydrase (hCA) isoenzymes I and II (hCA I and hCA II) were purified from fresh human blood erythrocytes with one-step affinity chromatography on Sepharose 4B-tyrosine-sulfanilamide. The inhibitory properties of the novel sulfamides on both isoenzymes were determined using the esterase activity with 4-nitrophenyl acetate (NPA) as substrate. The tested novel sulfamides derived from 1-aminoindanes and anilines effectively inhibited hCA I and II competitively in the nanomolar range. Among these compounds, the novel sulfamide derivative 17 showed the most potent inhibitory effect against hCA I (K-i: 153.88 nM), while sulfamide derivative 26 showed the highest inhibitory potential against hCA II (K-i: 117.80 nM).
Synthesis and Inhibitory Properties of Some Carbamates on Carbonic Anhydrase and Acetylcholine Esterase
(Taylor & Francis Ltd, 2016) Yilmaz, Suleyman; Akbaba, Yusuf; Ozgeris, Bunyamin; Kose, Leyla Polat; Goksu, Suleyman; Gulcin, Ilhami; Supuran, Claudiu T.
A series of carbamate derivatives were synthesized and their carbonic anhydrase I and II isoenzymes and acetylcholinesterase enzyme (AChE) inhibitory effects were investigated. All carbamates were synthesized from the corresponding carboxylic acids via the Curtius reactions of the acids with diphenyl phosphoryl azide followed by addition of benzyl alcohol. The carbamates were determined to be very good inhibitors against for AChE and hCA I, and II isoenzymes. AChE inhibition was determined in the range 0.209-0.291 nM. On the other hand, tacrine, which is used in the treatment of Alzheimer's disease possessed lower inhibition effect (K-i: 0.398 nM). Also, hCA I and II isoenzymes were effectively inhibited by the carbamates, with inhibition constants (Ki) in the range of 4.49-5.61 nM for hCA I, and 4.94-7.66 nM for hCA II, respectively. Acetazolamide, which was clinically used carbonic anhydrase (CA) inhibitor demonstrated Ki values of 281.33 nM for hCA I and 9.07nM for hCA II. The results clearly showed that AChE and both CA isoenzymes were effectively inhibited by carbamates at the low nanomolar levels.
Synthesis of Β-Lactams and Transformation to Β-Amino Acid Ethyl Ester Derivatives: Theoretical Calculations
(Pergamon-Elsevier Science Ltd, 2024) Akbaba, Yusuf; Cetinkaya, Yasin; Basceken, Sinan; Akincioglu, Akin; Goksu, Sueleyman
Because of the important biological properties of beta-amino acids in the present work, two new beta-amino acid ethyl ester derivatives were synthesized, and their mechanistic occurrence was investigated. The title compounds were synthesized from related tetralone derivatives containing bromine and methoxy groups. Tetralone derivatives were reduced to their benzyl alcohol derivatives with NaBH4, followed by elimination with p-toluenesulfonic acid (pTSA) to give the desired 1,2-dihydronaphthalene derivatives. The reactions of 1,2-dihydronaphthalenes with chlorosulfonyl isocyanate (CSI) afforded beta-lactams. beta-Amino acids were obtained from the reaction of beta-lactams with EtOH in HCl. Computational studies are concerned with synthesizing four-membered lactams (beta-lactam) formed by the reaction between 1,2-dihydronaphthalene derivatives and CSI. The mechanism of the formation of compounds has been elucidated using DFT at M06-2X.