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Chembiochem : a European Journal of... Dec 2022Epipolythiodioxopiperazines (ETPs) are fungal secondary metabolites that share a 2,5-diketopiperazine scaffold built from two amino acids and bridged by a sulfide... (Review)
Review
Epipolythiodioxopiperazines (ETPs) are fungal secondary metabolites that share a 2,5-diketopiperazine scaffold built from two amino acids and bridged by a sulfide moiety. Modifications of the core and the amino acid side chains, for example by methylations, acetylations, hydroxylations, prenylations, halogenations, cyclizations, and truncations create the structural diversity of ETPs and contribute to their biological activity. However, the key feature responsible for the bioactivities of ETPs is their sulfide moiety. Over the last years, combinations of genome mining, reverse genetics, metabolomics, biochemistry, and structural biology deciphered principles of ETP production. Sulfurization via glutathione and uncovering of the thiols followed by either oxidation or methylation crystallized as fundamental steps that impact expression of the biosynthesis cluster, toxicity and secretion of the metabolite as well as self-tolerance of the producer. This article showcases structure and activity of prototype ETPs such as gliotoxin and discusses the current knowledge on the biosynthesis routes of these exceptional natural products.
Topics: Biological Products; Gliotoxin; Multigene Family; Sulfides; Piperazines
PubMed: 35997236
DOI: 10.1002/cbic.202200341 -
Bioscience, Biotechnology, and... Jul 2022Brassinolide (BL) is a possible plant growth regulator in agriculture, but the presence of a steroid skeleton hampers the field application of BL in agriculture because...
Brassinolide (BL) is a possible plant growth regulator in agriculture, but the presence of a steroid skeleton hampers the field application of BL in agriculture because of its high synthetic cost. We discovered NSBR1 as the first nonsteroidal BL-like compound using in silico technology. Searching for more potent BL-like compounds, we modified the structure of NSBR1 with respect to 2 benzene rings and the piperazine ring. The activity of synthesized compounds was measured in Arabidopsis hypocotyl elongation. The propyl group of butyryl moiety of NSBR1 was changed to various alkyl groups, such as straight, branched, and cyclic alkyl chains. Another substituent, F, at the ortho position of the B ring toward the piperazine ring was changed to other substituents. A methyl group was introduced to the piperazine ring. Most of the newly synthesized compounds with the 3,4-(OH)2 group at the A ring significantly elongated the hypocotyl of Arabidopsis.
Topics: Arabidopsis; Arabidopsis Proteins; Brassinosteroids; Piperazines; Steroids, Heterocyclic
PubMed: 35687006
DOI: 10.1093/bbb/zbac074 -
Natural Product Research May 2020Phenazine-1-carboxylic acid (PCA) as a natural product which has significant inhibition effects against many soil-borne fungal phytopathogens in agricultural application...
Phenazine-1-carboxylic acid (PCA) as a natural product which has significant inhibition effects against many soil-borne fungal phytopathogens in agricultural application and has been registered in China as the fungicide against rice sheath blight. In order to find new higher fungicidal activities lead compounds and develop new eco-friendly agrochemicals, we introduced substructure piperazines which also have high biological activity into PCA, designed and synthesized a series of phenazine-1-carboxylic piperazine derivatives, and their structures were confirmed by H NMR and HRMS. Most compounds exhibited certain fungicidal activities. In particular, Compounds exhibited the activity against all the tested pathogenic fungi, such as , , , , oryzac Cavgra, with the EC value of 24.6μM, 42.9μM, 73.7μM, 73.8μM, 34.2μM, respectively, more potent activities than PCA (33.2μM, 81.5μM, 186.5μM, 176.4μM, 37.3μM). This result provided a highly active lead compound for the further structure optimization design.
Topics: Alternaria; Drug Evaluation, Preclinical; Fungicides, Industrial; Fusarium; Mass Spectrometry; Molecular Structure; Phenazines; Piperazines; Rhizoctonia; Structure-Activity Relationship
PubMed: 30698024
DOI: 10.1080/14786419.2018.1556656 -
Molecules (Basel, Switzerland) Jul 2023A series of novel Mannich bases were designed, synthesized, and screened for their antimicrobial activity. The target compounds were synthesized from...
A series of novel Mannich bases were designed, synthesized, and screened for their antimicrobial activity. The target compounds were synthesized from 4-(3-chlorophenyl)-5-(3-fluorophenyl)-2,4-dihydro-3-1,2,4-triazole-3-thione and different piperazine derivatives. The structures of the products were confirmed by H and C NMR and elemental analysis. The activity of piperazine derivatives against bacteria (Gram-positive: , , , , and ; Gram-negative: , , , and ) and yeasts (, , and ) was determined by the minimum inhibitory concentration and minimum bactericidal concentration values. Significant activity was observed against Gram-positive bacteria, mainly staphylococci (-) and bacteria of the genes of and (), as well as selected strains of Gram-negative bacteria, including bacteria of the family (), while all tested compounds showed high fungistatic activity against spp. yeasts, especially , with MICs ranging from 0.49 µg/mL () to 0.98 µg/mL () and 62.5 µg/mL (). In conclusion, the results obtained confirm the multidirectional antimicrobial activity of the newly synthesized piperazine derivatives. Furthermore, in silico studies suggest that the tested compounds are likely to have good oral bioavailability. The results obtained will provide valuable data for further research into this interesting group of compounds. The library of compounds obtained is still the subject of pharmacological research aimed at finding new interesting biologically active compounds.
Topics: Piperazine; Mannich Bases; Bacteria; Gram-Positive Bacteria; Microbial Sensitivity Tests; Gram-Negative Bacteria; Candida; Anti-Infective Agents; Anti-Bacterial Agents
PubMed: 37513434
DOI: 10.3390/molecules28145562 -
Ying Yong Sheng Tai Xue Bao = the... Jun 2023Synthetic fluoroquinolones (FQs) are the third most commonly used antibiotics in the world and play an extremely important role in antibacterial drugs. The excessive use...
Synthetic fluoroquinolones (FQs) are the third most commonly used antibiotics in the world and play an extremely important role in antibacterial drugs. The excessive use and discharge will alter ecological environment, with consequence on human health and global sustainable development. It is therefore of great significance for scientific use and management of FQs to systematically understand their biogeochemical behavior and eco-environmental effects. After drug administration in humans and animals, only a small part of FQs are transformed . The main transformation processes include formylation, acetylation, oxidation and cleavage of piperazine ring, defluorination and decarboxylation of aromatic core ring, . About 70% of the original drug and a small amount of transformed products would be migrated to the environment through excretion. After entering the environment, FQs and their transformation products mainly exist in environmental media such as water, soil and sediment, and undergo migration and transformation processes such as adsorption, photolysis and biodegradation. Adsorption facilitates transfer of FQs from medium to another. The photolysis mainly affects the C7-amine substituents of FQs, whereas the core structure of FQs remains intact. Biodegradation mainly refers to the degradation of FQs by microorganisms and microalgae, including piperazine modification of the piperazine ring such as acetylation and formylation, partial or complete ring cleavage, core structure decarboxylation, defluorination and conjugation formation. The migration and transformation processes of FQs cannot completely eliminate them from the environment. Instead, they would become "pseudo-persistent" pollutants, which seriously affect the behavior, growth and reproduction of algae, crustaceans and fish, change biogeochemical cycle, destroy aquatic environment, and stimulate microbial resistance and the generation of resistance genes. In the future, more in-depth studies should be conducted on the environmental behavior of FQs and their impacts on ecological environment, the risk assessment of microbial resistance and resistance genes of FQs, and the mechanism and effect of micro-biodegradation of FQs.
Topics: Animals; Humans; Fluoroquinolones; Climate; Anti-Bacterial Agents; Biodegradation, Environmental; Piperazines
PubMed: 37694431
DOI: 10.13287/j.1001-9332.202306.029 -
Dalton Transactions (Cambridge, England... Jan 2021The piperazine scaffold is a privileged structure frequently found in biologically active compounds. Piperazine nucleus is found in many marketed drugs in the realm of... (Review)
Review
The piperazine scaffold is a privileged structure frequently found in biologically active compounds. Piperazine nucleus is found in many marketed drugs in the realm of antidepressants (amoxapine), antipsychotics (bifeprunox), antihistamines (cyclizine and oxatomide), antifungals (itraconazole), antibiotics (ciprofloxacin), etc. This is one of the reasons why piperazine based compounds are gaining prominence in today's research. In addition to the ring carbons, substitution in the nitrogen atom of piperazine not only creates potential drug molecules but also makes it unique with versatile binding possibilities with metal ions. Piperazine ring-based compounds find their application in biological systems with antihistamine, anticancer, antimicrobial and antioxidant properties. They have also been successfully used in the field of catalysis and metal organic frameworks (MOFs). The present review focuses on the synthesis and application of different piperazine derivatives and their metal complexes having diverse applications.
Topics: Chemistry Techniques, Synthetic; Coordination Complexes; Ligands; Piperazine
PubMed: 33416816
DOI: 10.1039/d0dt03569f -
International Urology and Nephrology Feb 2022Piperazine ferulate, a derivative of ferulic acid has been widely used in clinical practice for cardiovascular and kidney diseases in China. The objective of this... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Piperazine ferulate, a derivative of ferulic acid has been widely used in clinical practice for cardiovascular and kidney diseases in China. The objective of this meta-analysis was to investigate the benefits by adding piperazine ferulate to angiotensin receptor blockers (ARBs) in diabetic nephropathy patients.
METHODS
PubMed, Embase, Cochrane Library, Wangfang, VIP, and CNKI database (until March 17, 2021) were comprehensively searched for randomized controlled trials investigating the effects of adding piperazine ferulate to ARBs in diabetic nephropathy patients.
RESULTS
Data were retrieved from 14 RCTs involving 1374 patients. When compared with ARBs alone, co-administration of piperazine ferulate and ARBs significantly reduced urinary albumin excretion rate (weighted mean differences [WMD] - 20.32 μg/min; 95% confidence interval [CI] - 28.45 to - 12.19), 24-h proteinuria (WMD - 91.08 mg; 95% CI - 107.24 to - 74.91), β2-microglobulin (standard mean difference [SMD] - 2.07; 95% CI - 2.51 to - 1.63), serum level of creatinine (WMD - 8.39 μmol/L; 95% CI - 11.87 to - 4.92), fibrinogen (WMD - 0.40 g/L; 95% CI - 0.46 to - 0.33), and plasma viscosity (WMD - 0.56 mPa s; 95% CI - 0.91 to - 0.21). Subgroup analysis showed that the effects of piperazine ferulate on UAER and serum creatinine were stronger in early diabetic nephropathy. However, piperazine ferulate had no significant effects on the serum blood urea nitrogen and fasting blood glucose.
CONCLUSION
Adding piperazine ferulate to ARBs may achieve additional renal protective benefits, particular in early diabetic nephropathy patients.
Topics: Angiotensin Receptor Antagonists; Diabetic Nephropathies; Drug Therapy, Combination; Humans; Piperazine; Randomized Controlled Trials as Topic
PubMed: 34191230
DOI: 10.1007/s11255-021-02927-2 -
Journal of Medicinal Chemistry Jul 2023In search of new dual-acting histamine H/sigma-1 receptor ligands, we designed a series of compounds structurally based on highly active ligands previously studied and...
In search of new dual-acting histamine H/sigma-1 receptor ligands, we designed a series of compounds structurally based on highly active ligands previously studied and described by our team. However, we kept in mind that within the previous series, a pair of closely related compounds, and , differing only in the piperazine/piperidine moiety in the structural core showed a significantly different affinity at sigma-1 receptors (σRs). Therefore, we first focused on an in-depth analysis of the protonation states of piperazine and piperidine derivatives in the studied compounds. In a series of 16 new ligands, mainly based on the piperidine core, we selected three lead structures (, , and ) for further biological evaluation. Compound showed a broad spectrum of analgesic activity in both nociceptive and neuropathic pain models based on the novel molecular mechanism.
Topics: Humans; Histamine; Receptors, Histamine H3; Ligands; Nociception; Receptors, sigma; Piperazine; Piperidines; Neuralgia; Structure-Activity Relationship; Sigma-1 Receptor
PubMed: 37418295
DOI: 10.1021/acs.jmedchem.3c00430 -
Pest Management Science Jul 2023The cucumber mosaic virus (CMV) is well-known for its expansive host range and distribution, resulting in a detrimental effect on agricultural production, thus making it...
BACKGROUND
The cucumber mosaic virus (CMV) is well-known for its expansive host range and distribution, resulting in a detrimental effect on agricultural production, thus making it imperative to implement measures for its control.
RESULTS
Novel compounds S1-S28 were synthesized by connecting trifluoromethyl pyridine, amide and piperazine scaffolds. Bioassays indicated that most of the synthesized compounds exhibited good curative effects against CMV, with half maximal effective concentration (EC ) values of compounds S1, S2, S7, S8, S10, S11, S15, and S28 being 119.6, 168.9, 197.6, 169.1, 97.9, 73.9, 224.4, and 125.2 μg mL , respectively, which were lower than the EC of ningnanmycin (314.7 μg mL ). Compounds S5 and S8 exhibited protective activities with EC of 170.8 and 95.0 μg mL , respectively, which were lower than ningnanmycin at 171.4 μg mL . The inactivation activities of S6 and S8 at 500 μg mL were remarkably high at 66.1% and 78.3%, respectively, surpassing that of ningnanmycin (63.5%). Additionally, their EC values were more favorable at 22.2 and 18.1 μg mL , respectively, than ningnanmycin (38.4 μg mL ). And molecular docking and molecular dynamics simulation showed compound S8 had better binding with CMV-coat protein, providing a possible explanation for the anti-CMV activity of compound S8.
CONCLUSIONS
Compound S8 showed a strong binding affinity to CMV-coat protein and impacted the self-assemble of CMV particles. Compound S8 could be a potential lead compound for discovering a new anti-plant virus candidate. © 2023 Society of Chemical Industry.
Topics: Tobacco Mosaic Virus; Molecular Docking Simulation; Antiviral Agents; Plant Viruses; Pyridines; Cucumovirus; Piperazines; Structure-Activity Relationship; Drug Design
PubMed: 36866809
DOI: 10.1002/ps.7429 -
Vnitrni Lekarstvi 2022Essential arterial hypertension is not a disease that would significantly adversely affect patients in their daily activities. At least mostly. Nonetheless, it has a...
Essential arterial hypertension is not a disease that would significantly adversely affect patients in their daily activities. At least mostly. Nonetheless, it has a significant negative impact on cardiovascular morbidity and mortality. The tight correlation with the degree of hypertension, the patients age and, of course, commorbidities and cardiovascular risk factors is obvious. Therefore, the goal of hypertensive therapy is not only to try to achieve optimal reduction of blood pressure, but in a broader sense to reduce the risk of the just mentioned consequences, i.e. to reduce morbidity and reduce mortality. The antihypertensive drug urapidil can also be used in pharmacotherapy, the brief description of which is the subject of this article.
Topics: Antihypertensive Agents; Blood Pressure; Humans; Hypertension; Piperazines
PubMed: 36220424
DOI: No ID Found