Heterocyclic Cathinones as Inhibitors of Kynurenine Aminotransferase II—Design, Synthesis, and Evaluation

Kynurenic acid is a neuroprotective metabolite of tryptophan formed by kynurenine aminotransferase (KAT) catalyzed transformation of kynurenine. However, its high brain levels are associated with cognitive deficit and with the pathophysiology of schizophrenia. Although several classes of KAT inhibitors have been published, the search for new inhibitor chemotypes is crucial for the process of finding suitable clinical candidates. Therefore, we used pharmacophore modeling and molecular docking, which predicted derivatives of heterocyclic amino ketones as new potential irreversible inhibitors of kynurenine aminotransferase II. Thiazole and triazole-based amino ketones were synthesized within a SAR study and their inhibitory activities were evaluated in vitro. The observed activities confirmed our computational model and, moreover, the best compounds showed sub-micromolar inhibitory activity with 2-alaninoyl-5-(4-fluorophenyl)thiazole having IC50 = 0.097 µM.

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Amide derivatives of Gallic acid: Design, synthesis and evaluation of inhibitory activities against in vitro α-synuclein aggregation

Bioorganic & Medicinal Chemistry ◽

10.1016/j.bmc.2020.115596 ◽

2020 ◽

Vol 28 (15) ◽

pp. 115596

Author(s):

Li Chen ◽

Guo-Long Huang ◽

Ming-Huan Lü ◽

Yun-Xiao Zhang ◽

Ji Xu ◽

...

Keyword(s):

Gallic Acid ◽

Design Synthesis ◽

Amide Derivatives ◽

Inhibitory Activities ◽

Derivatives Of

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Design, synthesis, molecular docking, and in vitro α-glucosidase inhibitory activities of novel 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines against yeast and rat α-glucosidase

Scientific Reports ◽

10.1038/s41598-021-91473-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Fariba Peytam ◽

Ghazaleh Takalloobanafshi ◽

Toktam Saadattalab ◽

Maryam Norouzbahari ◽

Zahra Emamgholipour ◽

...

Keyword(s):

Molecular Docking ◽

Docking Study ◽

Rat Small Intestine ◽

Molecular Docking Study ◽

Design Synthesis ◽

Mild Conditions ◽

Glucosidase Inhibitors ◽

Inhibitory Activities

AbstractIn an attempt to find novel, potent α-glucosidase inhibitors, a library of poly-substituted 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines 3a–ag have been synthesized through heating a mixture of 2-aminobenzimidazoles 1 and α-azidochalcone 2 under the mild conditions. This efficient, facile protocol has been resulted into the desirable compounds with a wide substrate scope in good to excellent yields. Afterwards, their inhibitory activities against yeast α-glucosidase enzyme were investigated. Showing IC50 values ranging from 16.4 ± 0.36 µM to 297.0 ± 1.2 µM confirmed their excellent potency to inhibit α-glucosidase which encouraged us to perform further studies on α-glucosidase enzymes obtained from rat as a mammal source. Among various synthesized 3-amino-2,4-diarylbenzo[4,5]imidazo[1,2-a]pyrimidines, compound 3k exhibited the highest potency against both Saccharomyces cerevisiae α-glucosidase (IC50 = 16.4 ± 0.36 μM) and rat small intestine α-glucosidase (IC50 = 45.0 ± 8.2 μM). Moreover, the role of amine moiety on the observed activity was studied through substituting with chlorine and hydrogen resulted into a considerable deterioration on the inhibitory activity. Kinetic study and molecular docking study have confirmed the in-vitro results.

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Design, synthesis and antibacterial evaluation of ocotillol derivatives with polycyclic nitrogen-containing groups

Future Medicinal Chemistry ◽

10.4155/fmc-2020-0364 ◽

2021 ◽

Author(s):

Yucheng Cao ◽

Kaiyi Wang ◽

Jiali Wang ◽

Haoran Cheng ◽

Mengxin Ma ◽

...

Keyword(s):

Antibacterial Activity ◽

Multidrug Resistant ◽

Inhibitory Effect ◽

Resistant Bacteria ◽

Design Synthesis ◽

In Vitro Antibacterial Activity ◽

Strong Inhibitory Effect ◽

Hospital Acquired ◽

Derivatives Of

Aim: With the increasing abuse of antibacterial drugs, multidrug-resistant bacteria have become a burden on human health and the healthcare system. To find alternative compounds effective against hospital-acquired methicillin-resistant Staphylococcus aureus (HA-MRSA), novel derivatives of ocotillol were synthesized. Methods & Results: Ocotillol derivatives with polycyclic nitrogen-containing groups were synthesized and evaluated for in vitro antibacterial activity. Compounds 36–39 exhibited potent antibacterial activity against hospital-acquired MRSA, with MIC = 8–64 μg/ml. Additionally, a combination of compound 37 and the commercially available antibiotic kanamycin showed synergistic inhibitory effects, with a fractional inhibitory concentration index of ≤0.375. Conclusion: Compound 37 has a strong inhibitory effect, and this derivative has potential for use as a pharmacological tool to explore antibacterial mechanisms.

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Design, synthesis and evaluation of belinostat analogs as histone deacetylase inhibitors

Future Medicinal Chemistry ◽

10.4155/fmc-2018-0587 ◽

2019 ◽

Vol 11 (21) ◽

pp. 2765-2778

Author(s):

Jie-Huan Zhang ◽

Madhusoodanan Mottamal ◽

Hai-Shan Jin ◽

Shanchun Guo ◽

Yan Gu ◽

...

Keyword(s):

Histone Deacetylase ◽

Active Compound ◽

Histone Deacetylase Inhibitors ◽

Hdac Inhibitors ◽

Antitumor Therapy ◽

Design Synthesis ◽

Inhibitory Activities ◽

Antiproliferative Activities

Aim: Histone deacetylase (HDAC) is an attractive target for antitumor therapy. Therefore, the development of novel HDAC inhibitors is warranted. Materials & methods: A series of HDAC inhibitors based on N-hydroxycinnamamide fragment was designed as the clinically used belinostat analog using amide as the connecting unit. All target compounds were evaluated for their in vitro HDAC inhibitory activities and some selected compounds were tested for their antiproliferative activities. Conclusion: Among them, compound 7e showed an IC50 value of 11.5 nM in inhibiting the HDAC in a pan-HDAC assay, being the most active compound of the series.

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Design, synthesis, molecular modelling and in vitro screening of monoamine oxidase inhibitory activities of novel quinazolyl hydrazine derivatives

Royal Society Open Science ◽

10.1098/rsos.200050 ◽

2020 ◽

Vol 7 (4) ◽

pp. 200050

Author(s):

Adel Amer ◽

Abdelrahman H. Hegazi ◽

Mohammed Khalil Alshekh ◽

Hany E. A. Ahmed ◽

Saied M. Soliman ◽

...

Keyword(s):

Mass Spectrometry ◽

Monoamine Oxidase ◽

In Vitro Screening ◽

Phenyl Substituent ◽

Design Synthesis ◽

Mao B ◽

Mao A ◽

Ft Ir ◽

Inhibitory Activities

A new series of N'-substituted benzylidene-2-(4-oxo-2-phenyl-1,4-dihydroquinazolin-3(2H)-yl)acetohydrazide ( 5a–5h ) has been synthesized, characterized by FT-IR, NMR spectroscopy and mass spectrometry and tested against human monoamine oxidase (MAO) A and B. Only (4-hydroxy-3-methoxybenzylidene) substituted compounds gave submicromolar inhibition of MAO-A and MAO-B. Changing the phenyl substituent to methyl on the unsaturated quinazoline ring ( 12a–12d ) decreased inhibition, but a less flexible linker ( 14a–14d ) resulted in selective micromolar inhibition of hMAO-B providing insight for ongoing design.

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Targeting Monoacylglycerol Lipase in Pursuit of Therapies for Neurological and Neurodegenerative Diseases

Molecules ◽

10.3390/molecules26185668 ◽

2021 ◽

Vol 26 (18) ◽

pp. 5668

Author(s):

Anca Zanfirescu ◽

Anca Ungurianu ◽

Dragos Mihai ◽

Denise Radulescu ◽

George Nitulescu

Keyword(s):

Neurodegenerative Diseases ◽

Monoacylglycerol Lipase ◽

Therapeutic Applications ◽

Irreversible Inhibitors ◽

Key Enzyme ◽

Synthetic Scaffolds ◽

Inflammatory Molecules ◽

Derivatives Of

Neurological and neurodegenerative diseases are debilitating conditions, and frequently lack an effective treatment. Monoacylglycerol lipase (MAGL) is a key enzyme involved in the metabolism of 2-AG (2-arachidonoylglycerol), a neuroprotective endocannabinoid intimately linked to the generation of pro- and anti-inflammatory molecules. Consequently, synthesizing selective MAGL inhibitors has become a focus point in drug design and development. The purpose of this review was to summarize the diverse synthetic scaffolds of MAGL inhibitors concerning their potency, mechanisms of action and potential therapeutic applications, focusing on the results of studies published in the past five years. The main irreversible inhibitors identified were derivatives of hexafluoroisopropyl alcohol carbamates, glycol carbamates, azetidone triazole ureas and benzisothiazolinone, whereas the most promising reversible inhibitors were derivatives of salicylketoxime, piperidine, pyrrolidone and azetidinyl amides. We reviewed the results of in-depth chemical, mechanistic and computational studies on MAGL inhibitors, in addition to the results of in vitro findings concerning selectivity and potency of inhibitors, using the half maximal inhibitory concentration (IC50) as an indicator of their effect on MAGL. Further, for highlighting the potential usefulness of highly selective and effective inhibitors, we examined the preclinical in vivo reports regarding the promising therapeutic applications of MAGL pharmacological inhibition.

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Design, Synthesis, and Cytotoxic Evaluation of Novel Lupane Triterpenoid Derived Hydroxamates

Natural Product Communications ◽

10.1177/1934578x20931967 ◽

2020 ◽

Vol 15 (6) ◽

pp. 1934578X2093196

Author(s):

Dang Thi Tuyet Anh ◽

Dinh Thi Cuc ◽

Le Nhat Thuy Giang ◽

Nguyen Thi Hien ◽

Vu Ngoc Doan ◽

...

Keyword(s):

Anticancer Agents ◽

Human Cancer ◽

Human Cancer Cell ◽

Design Synthesis ◽

Human Cancer Cell Lines ◽

Lupane Triterpenoids ◽

Lead Compounds ◽

Diphenyltetrazolium Bromide ◽

Derivatives Of

A series of new hydroxamate derivatives of lupane triterpenoids has been designed and successfully synthesized. The synthesized compounds were evaluated for their in vitro antitumor activity using the 3-[4,5-dimethylthiazol-2-yl]−2,5-diphenyltetrazolium bromide-based assay against the human cancer cell lines KB and HepG2. Most of these derivatives possess at least moderate cytotoxic activity and the hydroxamate derivative compounds 3c, 3e, 7a, and 15b could be lead compounds for further optimization to develop novel anticancer agents.

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Design, Synthesis, SAR Study, Antimicrobial and Anticancer Evaluation of Novel 2-Mercaptobenzimidazole Azomethine Derivatives

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557518666180903151849 ◽

2020 ◽

Vol 20 (15) ◽

pp. 1559-1571 ◽

Cited By ~ 6

Author(s):

Sumit Tahlan ◽

Balasubramanian Narasimhan ◽

Siong Meng Lim ◽

Kalavathy Ramasamy ◽

Vasudevan Mani ◽

...

Keyword(s):

Anticancer Activity ◽

Anticancer Agents ◽

Benzimidazole Derivatives ◽

Dilution Method ◽

Anticancer Activities ◽

Design Synthesis ◽

Standard Drug ◽

Wide Range ◽

Sar Study

Background: Various analogues of benzimidazole are found to be biologically and therapeutically potent against several ailments. Benzimidazole when attached with heterocyclic rings has shown wide range of potential activities. So, from the above provided facts, we altered benzimidazole derivatives so that more potent antagonists could be developed. In the search for a new category of antimicrobial and anticancer agents, novel azomethine of 2-mercaptobenzimidazole derived from 3-(2- (1H-benzo[d]imidazol-2-ylthio)acetamido)benzohydrazide were synthesized. Results and Discussion: The synthesized analogues were characterized by FT-IR, 1H/13C-NMR and MS studies as well C, H, N analysis. All synthesized compounds were evaluated for in vitro antibacterial activity against Gram-positive (B. subtilis), Gram-negative (E. coli, P. aeruginosa, K. pneumoniae and S. typhi) strains and in vitro antifungal activity against C. albicans and A. niger strains by serial dilution method, the minimum inhibitory concentration (MIC) described in μM/ml. The in vitro anticancer activity of synthesized compounds was determined against human colorectal carcinoma cell line (HCT- 116) using 5-fluorouracil as standard drug. Conclusion: In general, most of the synthesized derivatives exhibited significant antimicrobial and anticancer activities. Compounds 8, 10, 15, 16, 17, 20 and 22 showed significant antimicrobial activity towards tested bacterial and fungal strains and compound 26 exhibited significant anticancer activity.

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Design, Synthesis and Biological Evaluation of Anti-tuberculosis Agents based on Bedaquiline Structure

Medicinal Chemistry ◽

10.2174/1573406415666190613094433 ◽

2020 ◽

Vol 16 (5) ◽

pp. 703-714

Author(s):

Chengjun Wu ◽

Jinghan Luo ◽

Mengtong Wu ◽

Fanzhen Meng ◽

Zhiqiang Cai ◽

...

Keyword(s):

Molecular Docking ◽

Atp Synthase ◽

Docking Study ◽

Docking Studies ◽

Biological Evaluation ◽

Design Synthesis ◽

Mycobacterium Tuberculosis H37rv ◽

Inhibitory Activities ◽

Relationship Of

Background: Bedaquiline is a novel anti-tuberculosis drug that inhibits Mycobacterial ATP synthase. However, studies have found that bedaquiline has serious side effects due to high lipophilicity. Recently, the complete structure of ATP synthase was first reported in the Journal of Science. Objective: The study aimed to design, synthesise and carry out biological evaluation of antituberculosis agents based on the structure of bedaquiline. Methods: The mode of action of bedaquiline and ATP synthase was determined by molecular docking, and a series of low lipophilic bedaquiline derivatives were synthesized. The inhibitory activities of bedaquiline derivatives towards Mycobacterium phlei 1180 and Mycobacterium tuberculosis H37Rv were evaluated in vitro. A docking study was carried out to elucidate the structureactivity relationship of the obtained compounds. The predicted ADMET properties of the synthesized compounds were also analyzed. Results: The compounds 5c3, 6a1, and 6d3 showed good inhibitory activities (MIC=15.62 ug.mL-1). At the same time, the compounds 5c3, 6a1, and 6d3 also showed good drug-like properties through molecular docking and ADMET properties prediction. Conclusion: The results of in vitro anti-tuberculosis activity assays, docking studies and ADMET predictions indicate that the synthesized compounds have potential antifungal activity, with compounds 6a1 being further optimized and developed as lead compounds.

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