scholarly journals Comparison of the Inhibitory Binding Modes Between the Planar Fascaplysin and Its Nonplanar Tetrahydro-β-carboline Analogs in CDK4

2021 ◽  
Vol 9 ◽  
Author(s):  
Yan Liang ◽  
Huili Quan ◽  
Tong Bu ◽  
Xuedong Li ◽  
Xingang Liu ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Biological Activities ◽  
Mechanism Analysis ◽  
Binding Modes ◽  
Design Synthesis ◽  
Drug Candidates ◽  
Action Mechanisms ◽  
Marine Product ◽  
Inhibitory Activities ◽  
Key Residues

Fascaplysin is a natural marine product originating from sponges, attracting widespread attention due to its potential inhibitory activities against CDK4. However, its clinical application has been largely limited because of serious adverse effects caused by planar skeleton. To reduce the serious adverse effects, 18 tetrahydro-β-carboline analogs (compounds 6a-i and 7a-i) were designed and synthesized via breaking the planarity of fascaplysin, and the biological activities of the synthesized compounds were evaluated by MTT assay and CDK4/CycD3 enzyme inhibition assay. The title compounds showed varying degrees of inhibitory activities, especially the cytotoxicity of compound 6c against HeLa cells (IC50 = 1.03 ± 0.19 μM) with quite weak cytotoxicity toward the normal cells WI-38 (IC50 = 311.51 ± 56.06 μM), and the kinase inhibition test indicated that compound 6c was a potential CDK4 inhibitor. In order to further compare the action mechanisms of planar and nonplanar molecules on CDK4, the studied complexes of CDK4 bound with fascaplysin and three representative compounds (compound 6a-c) with bioactivities gradient were constructed by molecular docking and further verified through molecular dynamic simulation, which identified the key residues contributing to the ligands’ binding. By comparing the binding modes of the constructed systems, it could be found that the residues contributing significantly to compound 6c′s binding were highly consistent with those contributing significantly to fascaplysin’s binding. Through the design, synthesis of the nonplanar fascaplysin derivatives, and binding mechanism analysis, some valuable hints for the discovery of antitumor drug candidates could be provided.

scholarly journals Hybrid cis-stilbene Molecules: Novel Anticancer Agents

2019 ◽  
Vol 20 (6) ◽  
pp. 1300 ◽  
Author(s):  
Natalia Piekuś-Słomka ◽  
Renata Mikstacka ◽  
Joanna Ronowicz ◽  
Stanisław Sobiak
Keyword(s):  
Anticancer Agents ◽  
Biological Activities ◽  
Distinct Group ◽  
Design Synthesis ◽  
Drug Candidates ◽  
Structure Activity ◽  
Polymerization Inhibitor ◽  
Hybrid Molecules ◽  
Tubulin Polymerization Inhibitor ◽  
Pharmacologically Active

The growing interest in anticancer hybrids in the last few years has resulted in a great number of reports on hybrid design, synthesis and bioevaluation. Many novel multi-target-directed drug candidates were synthesized, and their biological activities were evaluated. For the design of anticancer hybrid compounds, the molecules of stilbenes, aromatic quinones, and heterocycles (benzimidazole, imidazole, pyrimidine, pyridine, pyrazole, quinoline, quinazoline) were applied. A distinct group of hybrids comprises the molecules built with natural compounds: Resveratrol, curcumin, coumarin, and oleanolic acid. In this review, we present the studies on bioactive hybrid molecules of a well-known tubulin polymerization inhibitor, combretastatin A-4 and its analogs with other pharmacologically active entities. The mechanism of anticancer activity of selected hybrids is discussed considering the structure-activity relationship.

Design, Synthesis and Biological Evaluation of the Novel Antitumor Agent Aurone Derivatives

2013 ◽  
Vol 781-784 ◽  
pp. 1235-1239
Author(s):  
Qian Nan Guo ◽  
Lei Lv ◽  
Yao Zhou ◽  
Peng Yu ◽  
Yuou Teng
Keyword(s):  
Biological Activities ◽  
Antitumor Agent ◽  
Biological Evaluation ◽  
The Novel ◽  
Pharmacological Activities ◽  
Design Synthesis ◽  
H Nmr ◽  
Wide Range ◽  
Inhibitory Activities ◽  
Synthesis And Biological Evaluation

Aurones belong to a class of heterocyclic flavonoids which contains a benzofuran element associated with a benzylidene linked in position 2. Aurones possess a wide range of pharmacological activities and biological activities, such as antitumor, antifungal, phytoalexin and so on. A novel series of 2-ayl-yl (5-methacrylate) aurone analogues were synthesized in six steps with the overall yield of 11%-13% and characterized by 1H NMR. Among the key intermediates and target compounds, 2-(2-furan-ylmethylene)-5-methacrylate-benzofuran-3(2H)-one (7a) and 2-(2-thienyl-ylmethylene)-5-methacrylate-benzofuran-3(2H)-one (7b) have never been reported before. Primary biological activities evaluation showed that 7a exhibited good inhibitory activities against K562 with an IC50 of 2.18 μM and against HepG2 with an IC50 of 3.95μM.

scholarly journals DESIGN, SYNTHESIS AND ANTIMICROBIAL STUDIES OF 5-BENZYLIDENE SUBSTITUTED RHODANINE CONTAINING HETEROCYCLES

2021 ◽  
pp. 28-34
Author(s):  
CICI MATHEW ◽  
BINDU SARASWATI ◽  
NAND LAL ◽  
JOYAMMA VARKEY
Keyword(s):  
Antibacterial Activity ◽  
Antifungal Activity ◽  
Candida Tropicalis ◽  
Candida Glabrata ◽  
Antimicrobial Agents ◽  
Biological Activities ◽  
Antimicrobial Activities ◽  
Design Synthesis ◽  
Drug Candidates ◽  
Antimicrobial Studies

Objective: The principal objective of the study was to synthesize and evaluate the biological activities of a novel class of 5-benzylidene substituted rhodanine derivatives as antimicrobial agents. Methods: All the synthesized compounds (D1-D10) were screened for their antimicrobial activities using microdilution methods as per the reported procedure. All compounds were evaluated as potential antimicrobial agents against gram-positive bacteria: Bacillus cereus, Staphylococcus aureus, gram negative bacteria: Escherichia coli Pseudomonas aeruginosa and Klebsiella pneumoniae Fungal cultures used in the study were Aspergillus niger, Candida albicans, Candida parapsilosis, Candida tropicalis and Candida glabrata. Results: Compound D6 showed good antifungal activity in the MIC range 16μg/ml against Candida tropicalis and Compound D10 showed good antifungal activity in the MIC range 16μg/ml against Candida glabrata. Compounds D2 and D5 showed good antibacterial activity at 32μg/ml. all the other compounds showed moderate antibacterial activity. Conclusion: Based on the above results, it can be concluded that the compounds may lead to the development of more potent antimicrobial drug candidates in the near future.

Click Reactions in Chemistry of Triterpenes - Advances Towards Development of Potential Therapeutics

2018 ◽  
Vol 25 (5) ◽  
pp. 636-658 ◽  
Author(s):  
Jan Pokorny ◽  
Lucie Borkova ◽  
Milan Urban
Keyword(s):  
Biological Activities ◽  
Synthetic Approach ◽  
Clinical Use ◽  
New Approach ◽  
Click Reactions ◽  
Drug Candidates ◽  
The Past ◽  
Low Toxicity ◽  
New Compounds ◽  
Potential Therapeutics

Triterpenoids are natural compounds with a large variety of biological activities such as anticancer, antiviral, antibacterial, antifungal, antiparazitic, antiinflammatory and others. Despite their low toxicity and simple availability from the natural resources, their clinical use is still severely limited by their higher IC50 and worse pharmacological properties than in the currently used therapeutics. This fact encouraged a number of researchers to develop new terpenic derivatives more suitable for the potential clinical use. This review summarizes a new approach to improve both, the activity and ADME-Tox properties by connecting active terpenes to another modifying molecules using click reactions. Within the past few years, this synthetic approach was well explored yielding a lot of great improvements of the parent compounds along with some less successful attempts. A large quantity of the new compounds presented here are superior in both activity and ADME-Tox properties to their parents. This review should serve the researchers who need to promote their hit triterpenic structures towards their clinical use and it is intended as a guide for the chemical synthesis of better drug candidates.

Recent Advances of In-Silico Modeling of Potent Antagonists for the Adenosine Receptors

2019 ◽  
Vol 25 (7) ◽  
pp. 750-773 ◽  
Author(s):  
Pabitra Narayan Samanta ◽  
Supratik Kar ◽  
Jerzy Leszczynski
Keyword(s):  
Drug Targets ◽  
Biological Activities ◽  
Scoring Function ◽  
Md Simulations ◽  
Energy Calculation ◽  
Binding Modes ◽  
Macromolecular Systems ◽  
In Silico Modeling ◽  
Mathematical Algorithms ◽  
The Impact

The rapid advancement of computer architectures and development of mathematical algorithms offer a unique opportunity to leverage the simulation of macromolecular systems at physiologically relevant timescales. Herein, we discuss the impact of diverse structure-based and ligand-based molecular modeling techniques in designing potent and selective antagonists against each adenosine receptor (AR) subtype that constitutes multitude of drug targets. The efficiency and robustness of high-throughput empirical scoring function-based approaches for hit discovery and lead optimization in the AR family are assessed with the help of illustrative examples that have led to nanomolar to sub-micromolar inhibition activities. Recent progress in computer-aided drug discovery through homology modeling, quantitative structure-activity relation, pharmacophore models, and molecular docking coupled with more accurate free energy calculation methods are reported and critically analyzed within the framework of structure-based virtual screening of AR antagonists. Later, the potency and applicability of integrated molecular dynamics (MD) methods are addressed in the context of diligent inspection of intricated AR-antagonist binding processes. MD simulations are exposed to be competent for studying the role of the membrane as well as the receptor flexibility toward the precise evaluation of the biological activities of antagonistbound AR complexes such as ligand binding modes, inhibition affinity, and associated thermodynamic and kinetic parameters.

Reactivity of Barbituric, Thiobarbituric Acids and Their Related Analogues: Synthesis of Substituted and Heterocycles-based Pyrimidines

2020 ◽  
Vol 24 (14) ◽  
pp. 1610-1642 ◽  
Author(s):  
Ahmed El-Mekabaty ◽  
Hassan A. Etman ◽  
Ahmed Mosbah ◽  
Ahmed A. Fadda
Keyword(s):  
Xanthine Oxidase ◽  
Multicomponent Reactions ◽  
Biological Activities ◽  
Present Review ◽  
Urease Inhibitors ◽  
Effective Catalyst ◽  
Inhibitory Activities ◽  
Catalyst Reusability ◽  
High Yields ◽  
Nano Catalysts

Barbituric, thiobarbituric acids and their related analogs are reactive synthons for the synthesis of drugs and biologically, and pharmaceutically active pyrimidines. The present review aimed to summarize the recent advances in the synthesis of different alkylsubstituted, fused cycles, spiro-, and binary heterocycles incorporated pyrimidine skeleton based on barbituric derivatives. In this sequence, the eco-friendly techniques under catalytic conditions were used for the diverse types of multicomponent reactions under different conditions for the synthesis of various types of heterocycles. Nano-catalysts are efficient for the synthesis of these compounds in high yields and effective catalyst reusability. The compounds are potent antibacterial, cytotoxic, xanthine oxidase inhibitory activities, and attend as urease inhibitors. The projected mechanisms for the synthesis of pyranopyrimidines, benzochromenopyrimidines, chromeno-pyranopyrimidines, spiroxyindoles, oxospiro-tricyclic furopyrimidines, pyrimidine-based monoand bicyclic pyridines were discussed. The potent and diverse biological activities for instance, antioxidant, antibacterial, cytotoxic, and xanthine oxidase inhibitory activities, as well as urease inhibitors, are specified.

Synthesis and Biological Activity of Quaternary Quinolinium Salts: A Review

2020 ◽  
Vol 23 (21) ◽  
pp. 2271-2294 ◽  
Author(s):  
Divya Utreja ◽  
Shivali Sharma ◽  
Akhil Goyal ◽  
Komalpreet Kaur ◽  
Sonia Kaushal
Keyword(s):  
Tyrosine Kinases ◽  
Biological Activities ◽  
Polymeric Materials ◽  
Tubulin Polymerization ◽  
Quinoline Derivatives ◽  
Heterocyclic Chemistry ◽  
Biological Profile ◽  
Drug Candidates ◽  
Anti Hiv ◽  
Quinolinium Salts

Heterocyclic chemistry is the only branch of chemistry that has applications in varied areas such as dyes, photosensitizers, coordination compounds, polymeric materials, biological, and many other fields. Quinoline and its derivatives have always engrossed both synthetic chemists and biologists because of their diverse chemical and pharmacological properties as these ring systems can be easily found in various natural products, especially in alkaloids. Among alkaloids, quinoline derivatives i.e. quinolinium salts have attracted much attention nowadays owing to their diverse biological profile such as antimicrobial, antitumor, antifungal, hypotensive, anti-HIV, analgesics and anti-inflammatory, etc. Quinoline and its analogs have recently been examined for their modes of function in the inhibition of tyrosine kinases, proteasome, tubulin polymerization, topoisomerase, and DNA repair. These observations have been guiding scientists for the expansion of new quinoline derivatives with improved and varied biological activities. Quinolinium salts have immense possibilities and scope to investigate these compounds as potential drug candidates. Therefore, we shall present a concise compilation of this work to aid in present knowledge and to help researchers explore an interesting quinoline class having medicinal potential.

Single Heterocyclic Compounds as Monoamine Oxidase Inhibitors: From Past to Present

2020 ◽  
Vol 20 (10) ◽  
pp. 908-920 ◽  
Author(s):  
Su-Min Wu ◽  
Xiao-Yang Qiu ◽  
Shu-Juan Liu ◽  
Juan Sun
Keyword(s):  
Monoamine Oxidase ◽  
Heterocyclic Compounds ◽  
Biological Activities ◽  
The Past ◽  
Structure Activity ◽  
Receptor Interactions ◽  
Heterocyclic Derivatives ◽  
Inhibitory Activities ◽  
Leading Compounds ◽  
Heterocyclic Moiety

Inhibitors of monoamine oxidase (MAO) have shown therapeutic values in a variety of neurodegenerative diseases such as depression, Parkinson’s disease and Alzheimer’s disease. Heterocyclic compounds exhibit a broad spectrum of biological activities and vital leading compounds for the development of chemical drugs. Herein, we focus on the synthesis and screening of novel single heterocyclic derivatives with MAO inhibitory activities during the past decade. This review covers recent pharmacological advancements of single heterocyclic moiety along with structure- activity relationship to provide better correlation among different structures and their receptor interactions.

Design, Synthesis and Pharmacological Evaluation of Novel Antiinflammatory and Analgesic O-Benzyloxime Compounds Derived From Natural Eugenol

2019 ◽  
Vol 16 (10) ◽  
pp. 1157-1166
Author(s):  
Rodrigo César da Silva ◽  
Fabiano Veiga ◽  
Fabiana Cardoso Vilela ◽  
André Victor Pereira ◽  
Thayssa Tavares da Silva Cunha ◽  
...  
Keyword(s):  
Formalin Test ◽  
Docking Studies ◽  
Paw Edema ◽  
Inhibitory Effects ◽  
Structural Pattern ◽  
Design Synthesis ◽  
Drug Candidates ◽  
Anti Inflammatory ◽  
Analgesic Activities ◽  
Cox 1

Background: : A new series of O-benzyloximes derived from eugenol was synthesized and was evaluated for its antinociceptive and anti-inflammatory properties. Methods: : The target compounds were obtained in good global 25-28% yields over 6 steps, which led us to identify compounds (Z)-5,6-dimethoxy-2,2-dimethyl-2,3-dihydro-1H-inden-1-one-O-(4- (methylthio)benzyloxime (8b), (Z)-5,6-dimethoxy-2,2-dimethyl-2,3-dihydro-1H-inden-1-one-O-4- bromobenzyloxime (8d) and (Z)-5,6-dimethoxy-2,2-dimethyl-2,3-dihydro-1H-inden-1-one-O-4- (methylsulfonyl)benzyloxime (8f) as promising bioactive prototypes. Results:: These compounds have significant analgesic and anti-inflammatory effects, as evidenced by formalin-induced mice paw edema and carrageenan-induced mice paw edema tests. In the formalin test, compounds 8b and 8f evidenced both anti-inflammatory and direct analgesic activities and in the carrageenan-induced paw edema, with compounds 8c, 8d, and 8f showing the best inhibitory effects, exceeding the standard drugs indomethacin and celecoxib. Conclusion: : Molecular docking studies have provided additional evidence that the pharmacological profile of these compounds may be related to inhibition of COX enzymes, with slight preference for COX-1. These results led us to identify the new O-benzyloxime ethers 8b, 8d and 8f as orally bioactive prototypes, with a novel structural pattern capable of being explored in further studies aiming at their optimization and development as drug candidates.

Design, Synthesis and Antifungal Activity of Novel 1-(Adamantan-1-yl) ethanone Oxime Esters

2020 ◽  
Vol 17 (5) ◽  
pp. 526-532
Author(s):  
Si Liu ◽  
Li-Zhi Niu ◽  
Yan-Hua Shi ◽  
Fu-Xian Wan ◽  
Lin Jiang
Keyword(s):  
Antifungal Activity ◽  
Biological Activities ◽  
Lead Compound ◽  
Design Synthesis ◽  
Antifungal Activities

Background: Oxime compounds, including oxime ethers and oxime esters, possess various biological activities. Many oxime ethers have been widely used in the fields of pesticides and medicines. However, oxime ethers are rarely used in the field of pesticides. Methods: We chose the excellent fungicide pyrifenox as the lead compound, integrated pyridinyl, adamantyl and benzoyl moieties into one molecule, while also designed and synthesized ten 1- (adamantan-1-yl)ethanone oxime esters containing pyridinyl moiety. Moreover, we also evaluated their preliminary antifungal activities against S. sclerotiorum and B. cinerea. Results: The target compounds were characterized by NMR, IR and HRMS. The preliminary bioactivity test showed that they exhibited some antifungal activity to S. sclerotiorum and B. cinerea, and EC50 values were in the range of 14.16-32.97 and 27.60-52.82 μg/mL, respectively. Conclusion: Some target compounds such as 3d, 3e, 3h and 3i, exhibited moderate activities against S. sclerotiorum, with EC50 values of 14.16-18.18 μg/mL.

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