scholarly journals Diphenylurea-derived cytokinin oxidase/dehydrogenase inhibitors for biotechnology and agriculture

2020 ◽  
Author(s):  
Jaroslav Nisler ◽  
David Kopečný ◽  
Zuzana Pěkná ◽  
Radka Končitíková ◽  
Radoslav Koprna ◽  
...  
Keyword(s):  
Plant Hormone ◽  
Biological Activities ◽  
Plant Biotechnology ◽  
Binding Mode ◽  
Crop Productivity ◽  
Culture Industry ◽  
Cytokinin Oxidase ◽  
Cytokinin Activity ◽  
Ic50 Values ◽  
Major Target

Abstract Increasing crop productivity is our major challenge if we are to meet global needs for food, fodder and fuel. Controlling the content of the plant hormone cytokinin is a method of improving plant productivity. Cytokinin oxidase/dehydrogenase (CKO/CKX) is a major target in this regard because it degrades cytokinins. Here, we describe the synthesis and biological activities of new CKX inhibitors derived mainly from diphenylurea. They were tested on four CKX isoforms from maize and Arabidopsis, where the best compounds showed IC50 values in the 10–8 M concentration range. The binding mode of the most efficient inhibitors was characterized from high-resolution crystal complexed structures. Although these compounds do not possess intrinsic cytokinin activity, we have demonstrated their tremendous potential for use in the plant tissue culture industry as well as in agriculture. We have identified a key substance, compound 19, which not only increases stress resistance and seed yield in Arabidopsis, but also improves the yield of wheat, barley and rapeseed grains under field conditions. Our findings reveal that modulation of cytokinin levels via CKX inhibition can positively affect plant growth, development and yield, and prove that CKX inhibitors can be an attractive target in plant biotechnology and agriculture.

Synthesis of 4-styrylpyrazoles and evaluation of their inhibitory effects on cyclin-dependent kinases

2021 ◽  
Vol 17 ◽  
Author(s):  
Daniel Toman ◽  
Radek Jorda ◽  
Haresh Ajani ◽  
Vladimír Kryštof ◽  
Petr Cankař
Keyword(s):  
Active Site ◽  
Kinase Inhibitors ◽  
Biological Activities ◽  
Flow Cytometric Analysis ◽  
Binding Mode ◽  
Cancer Drug ◽  
G1 Arrest ◽  
Inhibition Activity ◽  
Cyclin Dependent Kinases ◽  
Ic50 Values

Background: Cycle-regulating and transcriptional cyclin-dependent kinases (CDKs) are attractive targets in cancer drug development. Several CDK inhibitors have already been obtained or are close to regulatory approval for clinical applications. Objective: Phenylazopyrazole CAN508 has been described as the first selective CDK9 inhibitor with an IC50 of 350 nM. Since the azo-moiety is not a suitable functionality for drugs due to pharmacological reasons, the preparation of carbo-analogues of CAN508 with similar biological activities is desirable. The present work is focused on the synthesis of carbo-analogues similar to CAN508 and their CDK inhibition activity. Methods: Herein, the synthesis of 21 novel carbo analogues of CAN508 and their intermediates is reported. Subsequently, target compounds 8a – 8u were evaluated for protein kinase inhibition (CDK2/cyclin E, CDK4/cyclin D, CDK9/cyclin T) and antiproliferative activities in cell lines (K562, MCF-7, MV4-11). Moreover, the binding mode of derivative 8s in the active site of CDK9 was revealed by molecular docking. Results: Compounds 8a – 8u were obtained from key intermediate 7, which was prepared by linear synthesis involving Vilsmeier-Haack, Knoevenagel, Hunsdiecker, and Suzuki-Miyaura reactions. Styrylpyrazoles 8t and 8u were the most potent CDK9 inhibitors with IC50 values of approximately 1 µM. Molecular modelling suggested binding in the active site of CDK9 and CDK2. The flow cytometric analysis of MV4-11 cells treated with the most active styrylpyrazoles showed a significant G1-arrest. Conclusion: The prepared styrylpyrazoles showed inhibition activity towards CDKs and can provide a novel chemotype of kinase inhibitors.

Novel Iodinated Hydrazide-hydrazones and their Analogues as Acetyl- and Butyrylcholinesterase Inhibitors

2020 ◽  
Vol 20 (23) ◽  
pp. 2106-2117
Author(s):  
Martin Krátký ◽  
Šárka Štěpánková ◽  
Michaela Brablíková ◽  
Katarína Svrčková ◽  
Markéta Švarcová ◽  
...  
Keyword(s):  
Biological Activities ◽  
Structural Parameters ◽  
Covalent Binding ◽  
Docking Studies ◽  
Potent Inhibition ◽  
Brain Barrier Permeability ◽  
Electric Eel ◽  
Ic50 Values ◽  
Ellman’S Method

Background: Hydrazide-hydrazones have been known as scaffold with various biological activities including inhibition of acetyl- (AChE) and butyrylcholinesterase (BuChE). Cholinesterase inhibitors are mainstays of dementias’ treatment. Objective: Twenty-five iodinated hydrazide-hydrazones and their analogues were designed as potential central AChE and BuChE inhibitors. Methods: Hydrazide-hydrazones were synthesized from 4-substituted benzohydrazides and 2-/4- hydroxy-3,5-diiodobenzaldehydes. The compounds were investigated in vitro for their potency to inhibit AChE from electric eel and BuChE from equine serum using Ellman’s method. We calculated also physicochemical and structural parameters for CNS delivery. Results: The derivatives exhibited a moderate dual inhibition with IC50 values ranging from 15.1-140.5 and 35.5 to 170.5 μmol.L-1 for AChE and BuChE, respectively. Generally, the compounds produced a balanced or more potent inhibition of AChE. N'-[(E)-(4-Hydroxy-3,5-diiodophenyl)methylidene]-4- nitrobenzohydrazide 2k and 4-fluoro-N'-(2-hydroxy-3,5-diiodobenzyl)benzohydrazide 3a were the most potent inhibitors of AChE and BuChE, respectively. Structure-activity relationships were established, and molecular docking studies confirmed interaction with enzymes. Conclusion: Many novel hydrazide-hydrazones showed lower IC50 values than rivastigmine against AChE and some of them were comparable for BuChE to this drug used for the treatment of dementia. They interact with cholinesterases via non-covalent binding into the active site. Based on the BOILEDEgg approach, the majority of the derivatives met the criteria for blood-brain-barrier permeability.

Synthesis, Antioxidant and Antiurease Activities of Some New 5,6- dichloro-2-(4-fluorobenzyl)-1H-benzimidazole Derivatives Containing Furan, Oxadiazole, Triazole and Thiadiazole Moieties

2019 ◽  
Vol 16 (8) ◽  
pp. 939-947
Author(s):  
Hakan Bektas ◽  
Canan Albay ◽  
Emre Menteşe ◽  
Bahar Bilgin Sokmen ◽  
Zafer Kurt ◽  
...  
Keyword(s):  
Biological Activities ◽  
Benzimidazole Derivatives ◽  
Wide Range ◽  
Ic50 Values ◽  
Urease Inhibitory

Background:Benzimidazoles and its derivatives have been attracting interest for many years because of their biological activities. Benzimidazoles containing different heterocyclic moieties have wide range of biological activities such as antimicrobial, antioxidant, anticancer, antiviral, etc.Methods:In this study, some benzimidazole derivatives containing furan, oxadiazole, triazole and thiadiazole moieties have been synthesized and then evaluated for their antioxidant and antiurease activities.Results:The results showed that all the tested benzimidazoles indicated remarkable urease inhibitory potentials with IC50 values ranging between 0.303±0.03 to 0.591±0.08 µM.Conclusion:In conclusion, synthesized benzimidazole derivatives showed good antioxidant and antiurease activities. Heterocyclic groups on benzimidazole nucleus enhance the activities.

Naphthoquinone-based hydrazone hybrids: synthesis and potent activity against cancer cell lines

2020 ◽  
Vol 16 ◽  
Author(s):  
Délis Galvão Guimarães ◽  
Arlan de Assis Gonsalves ◽  
Larissa Araújo Rolim ◽  
Edigênia Cavalcante Araújo ◽  
Victória Laysna dos Anjos Santos ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Cell Lines ◽  
Cancer Cell ◽  
Biological Activities ◽  
Supporting Electrolyte ◽  
Cancer Cell Lines ◽  
Molecular Structures ◽  
Cytotoxic Activities ◽  
Electrochemical Studies ◽  
Ic50 Values

Background: Natural naphthoquinones have shown diversified biological activities including antibacterial, antifungal, antimalarial, and cytotoxic activities. However, they are also compounds with acute cytotoxicity, immunotoxicity, carcinogenesis, and cardio- and hepatotoxicity, then the modification at their redox center is an interesting strategy to overcome such harmful activity. Objective: In this study, four novel semisynthetic hydrazones, derived from the isomers α- and β-lapachones (α and β, respectively) and coupled with the drugs hydralazine (HDZ) and isoniazid (ACIL), were prepared, evaluated by electrochemical methods and assayed for anticancer activity. Method: The semisynthetic hydrazones were obtained and had their molecular structures established by NMR, IR, and MS. Anticancer activity was evaluated by cell viability determined by reduction of 3-(4,5-dimethyl-2-thiazol)-2,5-diphenyl-2H-tetrazolium bromide (MTT). The electrochemical studies, mainly cyclic voltammetry, were performed, in aprotic and protic media. Result: The study showed that the compounds 2, 3, and 4 were active against at least one of the cancer cell lines evaluated, being compounds 3 and 4 the most cytotoxic. Toward HL-60 cells, compound 3 was 20x more active than β-lapachone, and 3x more cytotoxic than doxorubicin. Furthermore, 3 showed an SI value of 39.62 for HL-60 cells. Compound 4 was active against all cancer cells tested, with IC50 values in the range 2.90–12.40 μM. Electrochemical studies revealed a profile typical of self-protonation and reductive cleavage, dependent on the supporting electrolyte. Conclusion: These results therefore indicate that compounds 3 and 4 are strong candidates as prototypes of new antineoplastic drugs.

scholarly journals Plant-Derived Nano and Microvesicles for Human Health and Therapeutic Potential in Nanomedicine

Pharmaceutics ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 498
Author(s):  
Mariaevelina Alfieri ◽  
Antonietta Leone ◽  
Alfredo Ambrosone
Keyword(s):  
Therapeutic Potential ◽  
Biological Activities ◽  
Plant Biotechnology ◽  
Bioactive Metabolites ◽  
Anticancer Activities ◽  
Long Distance ◽  
In Vivo Models ◽  
Therapeutic Tools

Plants produce different types of nano and micro-sized vesicles. Observed for the first time in the 60s, plant nano and microvesicles (PDVs) and their biological role have been inexplicably under investigated for a long time. Proteomic and metabolomic approaches revealed that PDVs carry numerous proteins with antifungal and antimicrobial activity, as well as bioactive metabolites with high pharmaceutical interest. PDVs have also been shown to be also involved in the intercellular transfer of small non-coding RNAs such as microRNAs, suggesting fascinating mechanisms of long-distance gene regulation and horizontal transfer of regulatory RNAs and inter-kingdom communications. High loading capacity, intrinsic biological activities, biocompatibility, and easy permeabilization in cell compartments make plant-derived vesicles excellent natural or bioengineered nanotools for biomedical applications. Growing evidence indicates that PDVs may exert anti-inflammatory, anti-oxidant, and anticancer activities in different in vitro and in vivo models. In addition, clinical trials are currently in progress to test the effectiveness of plant EVs in reducing insulin resistance and in preventing side effects of chemotherapy treatments. In this review, we concisely introduce PDVs, discuss shortly their most important biological and physiological roles in plants and provide clues on the use and the bioengineering of plant nano and microvesicles to develop innovative therapeutic tools in nanomedicine, able to encompass the current drawbacks in the delivery systems in nutraceutical and pharmaceutical technology. Finally, we predict that the advent of intense research efforts on PDVs may disclose new frontiers in plant biotechnology applied to nanomedicine.

scholarly journals The Repurposed Drugs Suramin and Quinacrine Cooperatively Inhibit SARS-CoV-2 3CLpro In Vitro

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 873
Author(s):  
Raphael J. Eberle ◽  
Danilo S. Olivier ◽  
Marcos S. Amaral ◽  
Ian Gering ◽  
Dieter Willbold ◽  
...  
Keyword(s):  
Binding Mode ◽  
Drug Candidates ◽  
Main Protease ◽  
Ic50 Values ◽  
Repurposed Drugs ◽  
Antiparasitic Drugs ◽  
Inhibitory Potential ◽  
Dynamics Simulations ◽  
Micromolar Range

Since the first report of a new pneumonia disease in December 2019 (Wuhan, China) the WHO reported more than 148 million confirmed cases and 3.1 million losses globally up to now. The causative agent of COVID-19 (SARS-CoV-2) has spread worldwide, resulting in a pandemic of unprecedented magnitude. To date, several clinically safe and efficient vaccines (e.g., Pfizer-BioNTech, Moderna, Johnson & Johnson, and AstraZeneca COVID-19 vaccines) as well as drugs for emergency use have been approved. However, increasing numbers of SARS-Cov-2 variants make it imminent to identify an alternative way to treat SARS-CoV-2 infections. A well-known strategy to identify molecules with inhibitory potential against SARS-CoV-2 proteins is repurposing clinically developed drugs, e.g., antiparasitic drugs. The results described in this study demonstrated the inhibitory potential of quinacrine and suramin against SARS-CoV-2 main protease (3CLpro). Quinacrine and suramin molecules presented a competitive and noncompetitive inhibition mode, respectively, with IC50 values in the low micromolar range. Surface plasmon resonance (SPR) experiments demonstrated that quinacrine and suramin alone possessed a moderate or weak affinity with SARS-CoV-2 3CLpro but suramin binding increased quinacrine interaction by around a factor of eight. Using docking and molecular dynamics simulations, we identified a possible binding mode and the amino acids involved in these interactions. Our results suggested that suramin, in combination with quinacrine, showed promising synergistic efficacy to inhibit SARS-CoV-2 3CLpro. We suppose that the identification of effective, synergistic drug combinations could lead to the design of better treatments for the COVID-19 disease and repurposable drug candidates offer fast therapeutic breakthroughs, mainly in a pandemic moment.

scholarly journals Biosynthesis, Characterization, and Biological Activities of Procyanidin Capped Silver Nanoparticles

2020 ◽  
Vol 11 (3) ◽  
pp. 66
Author(s):  
Umar M. Badeggi ◽  
Jelili A. Badmus ◽  
Subelia S. Botha ◽  
Enas Ismail ◽  
Jeanine L. Marnewick ◽  
...  
Keyword(s):  
Silver Nanoparticles ◽  
Food Packaging ◽  
Antioxidant Activities ◽  
Biological Activities ◽  
Bacterial Species ◽  
Bactericidal Effect ◽  
Total Extract ◽  
Selected Area Electron Diffraction ◽  
Ic50 Values ◽  
Inhibitory Activities

In this study, procyanidin dimers and Leucosidea sericea total extract (LSTE) were employed in the synthesis of silver nanoparticles (AgNPs) and characterized by ultraviolet-visible (UV-Visible) spectroscopy, high-resolution transmission electron microscopy (HRTEM), selected area electron diffraction (SAED), X-ray diffraction (XRD), and dynamic light scattering (DLS) techniques. AgNPs of about 2–7 nm were obtained. DLS and stability evaluations confirmed that the AgNPs/procyanidins conjugates were stable. The formed nanoparticles exhibited good inhibitory activities against the two enzymes studied. The IC50 values against the amylase enzyme were 14.92 ± 1.0, 13.24 ± 0.2, and 19.13 ± 0.8 µg/mL for AgNPs coordinated with LSTE, F1, and F2, respectively. The corresponding values for the glucosidase enzyme were 21.48 ± 0.9, 18.76 ± 1.0, and 8.75 ± 0.7 µg/mL. The antioxidant activities were comparable to those of the intact fractions. The AgNPs also demonstrated bacterial inhibitory activities against six bacterial species. While the minimum inhibitory concentrations (MIC) of F1-AgNPs against Pseudomonas aeruginosa and Staphylococcus aureus were 31.25 and 15.63 µg/mL respectively, those of LSTE-AgNPs and F2-AgNPs against these organisms were both 62.50 µg/mL. The F1-AgNPs demonstrated a better bactericidal effect and may be useful in food packaging. This research also showed the involvement of the procyanidins as reducing and capping agents in the formation of stable AgNPs with potential biological applications.

Design, Synthesis and Docking Studies of Thioimidazolyl Diketoacid Derivatives Targeting HIV-1 Integrase

2021 ◽  
Vol 17 ◽  
Author(s):  
Nafiseh Karimi ◽  
Rouhollah Vahabpour Roudsari ◽  
Zahra Hajimahdi ◽  
Afshin Zarghi
Keyword(s):  
Drug Target ◽  
Enzyme Assay ◽  
Binding Mode ◽  
Docking Studies ◽  
Integrase Inhibitors ◽  
Design Synthesis ◽  
Ic50 Values ◽  
Novel Structures ◽  
Anti Hiv ◽  
Hiv 1

Background: Integrase enzyme is a validated drug target to discover novel structures as anti-HIV-1 agents. Objective: Novel series of thioimidazolyl diketo acid derivatives characterizing various substituents at N-1 and 2-thio positions of central ring were developed as HIV-1 integrase inhibitors. Results: The obtained molecules were evaluated in the enzyme assay, displaying promising integrase inhibitory activity with IC50 values ranging from 0.9 to 7.7 M. The synthesized compounds were also tested for antiviral activity and cytotoxicity using HeLa cells infected by the single-cycle replicable HIV-1 NL4-3. Conclusion: The most potent compound was 18i with EC50=19 µM, IC50 0.9 µM and SI= 10.5. Docking studies indicated that the binding mode of the active molecule is well aligned with the known HIV-1 integrase inhibitors.

scholarly journals Two Novel Quassinoid Glycosides with Antiviral Activity from the Samara of Ailanthus altissima

Molecules ◽  
2020 ◽  
Vol 25 (23) ◽  
pp. 5679
Author(s):  
Qing-Wei Tan ◽  
Jian-Cheng Ni ◽  
Jian-Ting Shi ◽  
Jian-Xuan Zhu ◽  
Qi-Jian Chen
Keyword(s):  
Data Analysis ◽  
Herbal Medicine ◽  
Inhibitory Concentration ◽  
Biological Activities ◽  
Virus Multiplication ◽  
Ailanthus Altissima ◽  
Inhibitory Effects ◽  
Traditional Herbal Medicine ◽  
Virus Activity ◽  
Ic50 Values

Phytochemistry investigations on Ailanthus altissima (Mill.) Swingle, a Simaroubaceae plant that is recognized as a traditional herbal medicine, have afforded various natural products, among which C20 quassinoid is the most attractive for their significant and diverse pharmacological and biological activities. Our continuous study has led to the isolation of two novel quassinoid glycosides, named chuglycosides J and K, together with fourteen known lignans from the samara of A. altissima. The new structures were elucidated based on comprehensive spectra data analysis. All of the compounds were evaluated for their anti-tobacco mosaic virus activity, among which chuglycosides J and K exhibited inhibitory effects against the virus multiplication with half maximal inhibitory concentration (IC50) values of 56.21 ± 1.86 and 137.74 ± 3.57 μM, respectively.

scholarly journals In Vitro Study of Multi-Therapeutic Properties of Thymus bovei Benth. Essential Oil and Its Main Component for Promoting Their Use in Clinical Practice

2018 ◽  
Vol 7 (9) ◽  
pp. 283 ◽  
Author(s):  
Sherif Hassan ◽  
Kateřina Berchová-Bímová ◽  
Miroslava Šudomová ◽  
Milan Malaník ◽  
Karel Šmejkal ◽  
...  
Keyword(s):  
Gas Chromatography ◽  
Clinical Practice ◽  
Essential Oil ◽  
Biological Activities ◽  
Structural Parameters ◽  
Antihypertensive Agents ◽  
Gas Chromatography Mass Spectrometry ◽  
Ic50 Values ◽  
Main Component

Thymus bovei Benth. (TB) is an important plant in the traditional medicine of the Mediterranean region. This study investigates the health-promoting properties of TB essential oil (TB-EO) for its possible use in clinical practice with regards to its cytotoxic, anti-herpes simplex virus type 2 (HSV-2), and antihypertensive (through inhibition of human angiotensin-converting enzyme; ACE) properties. The phytochemical profile of EO (99.9%) was analyzed by Gas Chromatography with Flame-Ionization Detection (GC-FID) and Gas Chromatography-Mass Spectrometry (GC-MS). In this study, all biological methods were performed at the level of in vitro studies. The results showed that TB-EO exerted remarked cytotoxic properties against human cervical carcinoma cells, colon cancer cells, and lung adenocarcinoma cells with the half-maximal inhibitory concentration (IC50) values of 7.22, 9.30, and 8.62 µg/mL, respectively, in comparison with that of standard anticancer drug cisplatin with IC50 values of 4.24, 5.21, and 5.43 µg/mL, respectively. Fascinatingly, TB-EO showed very weak cytotoxicity on the healthy human fetal lung fibroblast cells with an IC50 value of 118.34 µg/mL compared with that of cisplatin (IC50 = 10.08 µg/mL). TB-EO, its main component geraniol, TB-EO combined with acyclovir (ACV) along with standard ACV, have displayed pronounced inhibitory properties against the replication of HSV-2 with the half-maximal effective concentration (EC50) values of 2.13, 1.92, 0.81 and 1.94 µg/mL, respectively, with corresponding selectivity indices (SI) 98.59, 109.38, 259.26 and 108.25, respectively. TB-EO and geraniol at a concentration of 15 µg/mL showed prominent inhibitory activities against ACE with % of inhibition 95.4% and 92.2%, respectively, compared with that of standard inhibitor captopril (99.8%; 15 µg/mL). Molecular docking studies were performed to unveil the mechanism of action of geraniol as well as structural parameters necessary for anti-HSV-2 activity (through the inhibition of HSV-2 protease) and ACE inhibition. This is the first report on the chemical composition of Egyptian TB-EO along with the above-mentioned biological activities. Our results may be considered as novel findings in the course of a search for new and active anticancer, anti-HSV-2 and antihypertensive agents, and expand the medicinal value of this plant and its phytochemicals in clinical practice.

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