Synthesis, characterization and docking studies of new chalcone derivatives carrying propargyl side chain as a monoaminoxidase inhibitor

Monoamin oksidazlar (MAO), endojen ve ekzojen aminlerin oksidatif deaminasyonundan sorumlu enzim ailesidir. MAO-A ve MAO-B olarak isimlendirilen iki izoformdan oluşan MAO enzimi nörotransmiterlerin metabolizmasındaki rollerinden dolayı nöropsikiyatrik ve nörodejeneratif bozuklukların tedavisi için ilaçların geliştirilmesinde önemli hedeflerdir. Özellikle MAO-B inhibitörlerinin Parkinson hastalığı (PH) ve Alzheimer hastalığı (AH) gibi en sık görülen nörodejeneratif hastalıkların tedavisinde sıklıkla tercih edildiği bilinmektedir. Bu amaçla, bu çalışma kapsamında yeni propargilşalkon türevleri sentezlenmiş ve yapı tayinleri 1H-NMR, 13C-NMR ve yüksek çözünürlüklü kütle spektroskopisi (HRMS) metotları kullanılarak aydınlatılmıştır. İn vitro aktivite testleri sonucunda elde edilen veriler 2c kodlu bileşiğin MAO-B inhibitörü olarak umut vaat edici olduğunu ortaya koymuştur. Gerçekleştirilen moleküler modelleme çalışmaları ile bileşik 2c’nin hMAO-B enzim aktif bölgesindeki bağlanma ve etkileşim noktaları belirlenmiştir.Monoamine oxidases (MAO) are a family of enzymes responsible for the oxidative deamination of endogenous and exogenous amines. The MAO enzyme, which consists of two isoforms named MAO-A and MAO-B, are important targets in the development of drugs for the treatment of neuropsychiatric and neurodegenerative disorders due to their role in the metabolism of neurotransmitters. It is known that MAO-B inhibitors are frequently preferred in the treatment of the most common neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD). For this purpose, within the scope of this study, new propargyl-chalcone derivatives were synthesized and the structure determinations were elucidated using 1H-NMR, 13C-NMR and high-resolution mass spectroscopy (HRMS) methods. The data obtained as a result of in vitro activity tests showed that the compound 2c is promising as a selective MAO-B inhibitor. With the molecular modelling studies carried out, the binding and interaction points of the compound 2c in the hMAO-B enzyme active site were determined

Bazı benzotiyazol türevlerinin antifungal aktivitesinin değerlendirilmesi

The antifungal activity of the previously synthesized compounds was evaluated in order to provide solutions to the candida-induced diseases in animals. In the present study, 10 benzothiazole derivatives (4a-4j) were resynthesized to evaluate their antifungal activity. IR, 1HNMR, 13C-NMR and HRMS (Infrared Spectroscopy, 1H Nuclear Magnetic Resonance Spectroscopy, 13C Nuclear Magnetic Resonance Spectroscopy, High Resolution Mass Spectrometry) spectroscopic methods, determined the structure of the synthesized compounds. MIC50(Minimum Inhibitory Concentration) values of the re-synthesized compounds against Candida species were evaluated by in vitro experiments. As a result of activity studies, it was found that compounds 4c and 4d showed significant activity. Compound 4d was found to be the most potent derivative against Candida krusei with a MIC50 value of 1.95 µg / mL.Hayvanlarda oluşan candida kaynaklı hastalıklara çözüm üretmek amacıyla daha önceden sentezi yapılmış bileşikler benzer metot kullanarak tekrar sentezlenmiş ve antifungal etkinlikleri değerlendirilmiştir. Mevcut çalışmada, 10 tane benzotiyazol türevi bileşik (4a-4j), antifungal aktivitelerini değerlendirmek üzere yeniden sentezlenmiştir. Sentezlenen bileşiklerin yapı tanımlamaları IR, 1HNMR, 13C-NMR ve HRMS (Kızılötesi Spektroskopi, 1H Nükleer Manyetik Rezonans Spektroskopisi, 13C Nükleer Manyetik Rezonans Spektroskopisi, Yüksek Çözünürlüklü Kütle Spektrometresi) spektroskopik yöntemleri kullanılarak gerçekleştirilmiştir. Yeniden sentezlenmiş bileşiklerin Candida türlerine karşı MIC50 (Minimum İnhibitör Konsantrasyon) değerleri in vitro deneyler yapılarak değerlendirilmiştir. Yapılan aktivite çalışmaları sonucunda 4c ve 4d bileşikleri önemli aktivite göstermiştir. 4d bileşiğinin Candida krusei’ye karşı 1.95 µg / mL MIC50 değeri ile güçlü bir türev olduğu bulunmuştur

Synthesis and Biological Evaluation of Some Novel Dithiocarbamate Derivatives

18 novel dithiocarbamate derivatives were synthesized in order to investigate their inhibitory potency on acetylcholinesterase enzyme and antimicrobial activity. Structures of the synthesized compounds were elucidated by spectral data and elemental analyses. The synthesized compounds showed low enzyme inhibitory activity. However, they displayed good antimicrobial activity profile. Antibacterial activity of compounds 4a, 4e, and 4p (MIC = 25 μg/mL) was equal to that of chloramphenicol against Klebsiella pneumoniae (ATCC 700603) and Escherichia coli (ATCC 35218). Most of the compounds exhibited notable antifungal activity against Candida albicans (ATCC 10231), Candida glabrata (ATCC 90030), Candida krusei (ATCC 6258), and Candida parapsilosis (ATCC 7330). Moreover, compound 4a, which carries piperidin-1-yl substituent and dimethylthiocarbamoyl side chain as variable group, showed twofold better anticandidal effect against all Candida species than reference drug ketoconazole

Synthesis, Anticandidal Activity and Molecular Docking Study of Some New Imidazole Derivatives

The azole pharmacophore is still regarded as a viable lead structure for the synthesis of more effective antifungal agents [1–3]. [...

Design, Synthesis and Biological Evaluation of Novel N-Pyridyl-Hydrazone Derivatives as Potential Monoamine Oxidase (MAO) Inhibitors

A new series of N-pyridyl-hydrazone derivatives was synthesized by using a simple and efficient method. The final compounds obtained were screened for their inhibitory potency against monoamine oxidase (MAO) A and B. The newly synthesized compounds 2a–2n specifically inhibited monoamine oxidases, displaying notably low IC50 values. Compounds 2i and 2j, with a CF3 and OH group on the 4-position of the phenyl ring, respectively, showed considerable MAO-A and MAO-B inhibitory activities. Compounds 2k, 2l and 2n, with N-methylpyrrole, furan and pyridine moieties instead of the phenyl ring, were the most powerful and specific inhibitors of MAO-A, with IC50 values of 6.12 μM, 10.64 μM and 9.52 μM, respectively. Moreover, these active compounds were found to be non-cytotoxic to NIH/3T3 cells. This study supports future studies aimed at designing MAO inhibitors to obtain more viable medications for neurodegenerative disorders, such as Parkinson’s disease

Synthesis and Anticandidal Activity of New Imidazole Derivatives

During the last few years, there has been an increased awareness of morbidity and mortality related to invasive and systemic fungal disease because of resistant fungi and immunocompromised infections, for instance, AIDS. [...

Novel Thiosemicarbazone Derivatives: In Vitro and In Silico Evaluation as Potential MAO-B Inhibitors

MAO-B inhibitors are frequently used in the treatment of neurodegenerative diseases such as Parkinson’s and Alzheimer’s. Due to the limited number of compounds available in this field, there is a need to develop new compounds. In the recent works, it was shown that various thiosemicarbazone derivatives show hMAO inhibitory activity in the range of micromolar concentration. It is thought that benzofuran and benzothiophene structures may mimic structures such as indane and indanone, which are frequently found in the structures of such inhibitors. Based on this view, new benzofuran/benzothiophene and thiosemicarbazone hybrid compounds were synthesized, characterized and screened for their hMAO-A and hMAO-B inhibitory activity by an in vitro fluorometric method. The compounds including methoxyethyl substituent (2b and 2h) were found to be the most effective agents in the series against MAO-B enzyme with the IC50 value of 0.042 ± 0.002 µM and 0.056 ± 0.002 µM, respectively. The mechanism of hMAO-B inhibition of compounds 2b and 2h was investigated by Lineweaver–Burk graphics. Compounds 2b and 2h were reversible and non-competitive inhibitors with similar inhibition features as the substrates. The Ki values of compounds 2b and 2h were calculated as 0.035 µM and 0.046 µM, respectively, with the help of secondary plots. The docking study of compound 2b and 2h revealed that there is a strong interaction between the active sites of hMAO-B and analyzed compound

Synthesis and Evaluation of N-[1-(((3,4-Diphenylthiazol-2(3H)-ylidene)amino)methyl)cyclopentyl]acetamide Derivatives for the Treatment of Diseases Belonging to MAOs

A series of N-[1-(((3,4-diphenylthiazol-2(3H)-ylidene)amino)methyl)cyclopentyl]acetamide derivatives (4a-4i) were synthesized in good yield and assayed for their inhibitory potency against monoamine oxidase (MAO) isoforms. Structures of newly synthesized compounds were characterized by IR, 1H-NMR, 13C-NMR, and mass spectroscopic methods. The inhibitory activity of compounds (4a-4i) against hMAO-A and hMAO-B enzymes was elucidated by using in vitro fluorometric method using Amplex Red® reagent. In the hMAO-A inhibition assay, compounds 4a, 4b, 4c, and 4i exhibited similar activity with standard drug moclobemide (IC50 = 6.061 ± 0.262 µM) with IC50 values of 7.06 ± 0.18 µM, 6.56 ± 0.20 µM, 6.78 ± 0.15 µM, and 7.09 ± 0.17 µM, respectively. According to hMAO-B inhibition results, compounds 4a, 4b, and 4c displayed significant activity with IC50 values of 0.42 ± 0.012 µM, 0.36 ± 0.014 µM, and 0.69 ± 0.020 µM, respectively. In the wake of all these results, it was understood that compound 4b was found to be the most potent derivative in the series against both isoforms and selective as MAO-B inhibitor. The cytotoxicity test was performed for compounds 4a, 4b, and 4c, and it was found that these compounds were noncytotoxic at the concentration of their IC50 values. Also, enzyme kinetic and docking studies of compound 4b were performed against MAO-B. It was observed that 4b showed a reversible and noncompetitive inhibition type. The important binding modes of this compound with active site of hMAO-B were shown owing to in silico studies

Synthesis and Biological Evaluation of New Cholinesterase Inhibitors for Alzheimer’s Disease

Alzheimer’s disease (AD) is a neurodegenerative disorder mostly influencing the elderly, and causes death due to dementia. The main pathogenic feature connected with the progression of this multifactorial disease is the weakening of the cholinergic system in the brain. Cholinesterase (ChE) inhibitors are recognized as one of the choices in the treatment of AD. The inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were approved as a therapeutic strategy to reduce the symptoms of AD and prevent its progression. The capacity of BChE is not completely known yet; rather, it is accepted to assume a part in a few disorders such as AD. Thus, BChE inhibitors may have a greater role for the treatment of AD in the future. In the present study, 2-(9-acridinylamino)-2-oxoethyl piperazine/piperidine/morpholinecarbodithioate derivatives were synthesized in order to investigate anticholinesterase activity. Eight derivatives demonstrated a specific and promising action against BChE. Furthermore, compound 4n showed inhibitory activity against both enzymes. It was found that the active compounds were well tolerated in the cytotoxicity test. Possible interactions between the lead compound, 4n, and the BChE enzyme were determined through a docking study. The findings obtained within this paper will contribute to the development of new and effective synthetic anti-Alzheimer compounds, and will ideally encourage future screening against AD