Synthesis of Novel Isoxazole-contained Analogues of Losartan

Losartan 1 (Dup-753) is a nonpeptide angiotensin II receptor (type AT1) antagonist discovered by Duncia, J.V. et al. 1 in 1990 and its potassium salt (cozaar) has been marketed as an antihypertensive since 1995 2. 1 2 Starting from Dup-753, a great number of structural related compounds have been prepared by several laboratories and several antihypertensive drugs have been developed3. In order to find new and more active compounds, a novel type of Losartan analogues 2 was designed and syn…     

Design,synthesis and biological evaluation of novel phthalazinone acridine derivatives as dual PARP and Topo inhibitors for potential anticancer agents

In this study,we designed and synthesized a series of phthalazinone acridine derivatives as dual PARP and Topo inhibitors.MTT assays indicated that most of the compounds significantly inhibited multiple cancer cells proliferation.In addition,all the compounds displayed Topo Ⅱ inhibition activity at 10 mol/L,and also possessed good PARP-1 inhibitory activities.Subsequent mechanistic studies showed that compound 9 a induced remarkable apoptosis and caused prominent S cell cycle arrest in HCT116 cells.Our study suggested that 9 a inhibiting Topo and PARP concurrently can be a potential lead compound for cancer therapy.     

Synthesis and biological evaluation of novel derivatives of desloratadine

Series of novel derivatives of desloratadine designed as arginine vasopressin receptor antagonists were synthesized and structurally characterized by melting points,~1H NMR and HRMS.Their in vivo diuretic activities were evaluated on rats,and several target compounds showed promising diuretic results, especially compounds 8,18,27 and 31.Further in vitro bonding assay and cAMP assay showed that these compounds had a higher affinity to vasopressin V2 receptor than VI a receptor.Our studies indicated that desloratadine may be an active substructure for novel arginine vasopressin receptor antagonist development.     

Silica-supported Thionyl Chloride-assisted Synthesis and Bioassay of Novel Tetrazinan-3-thione and 3-Oxo-pyrazolidine-4-carbonitrile Derivatives of Steroids

A series of tetrazinan-3-thione and 3-oxo-pyrazolidine-4-carbonitrile derivatives of steroids（1-3） were synthesized with silica-chloride as a heterogeneous catalyst.The synthesized compounds 4-9 were obtained in substantial yields.In vitro evaluation of anticancer and antioxidant activity of the synthesized compounds was carried out via 3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyltetrazolium bromide（MTT） and 1,1-diphenyl-2-picrylhydrazyl（DPPH）assays,respectively.Compound 6 exhibited promising anti-proliferative activity towards a panel of cancer cell lines.The significant activity of compound 6 was further ascertained on structural,molecular modelling and docking studies.This study may provide a valuable insight into the further design and development of more potent biologically active compounds.     

铋三氟甲磺酸酯:用于一锅多组分反应合成具有生物活性的香豆素化合物的高效催化剂（英文）

A series of coumarin-chalcone hybrid compounds and coumarins linked to pyrazoline was synthesized in good yield and short time using a simple and efficient method. This method involved the one-pot reaction of salicylaldehyde, an α-ketoester and an aromatic aldehyde(in the case of the coumarin-chalcone derivatives) in addition to hydrazine hydrate(in the case of the pyrazolyl coumarins) in the presence of a catalytic amount of bismuth triflate [Bi(OTf)3, 5 mol%]. The synthesized compounds showed scavenging activity towards the free radical 2,2-diphenyl-1-picrylhydrazyl. All compounds were characterized using IR, 1H NMR and 13 C NMR spectroscopy.     

Studies on Synthesis and Biological Activities of Novel Triazole Compounds Containing Pyrimidine or N, N－Dialkyldithiocarbamate Ring

Twelve of the title compounds were synthesized. Their structures were identified by means of IR, EA, IH NMR and MS. The IR spectra clearly show that the absorptions in the regions of 1716—1666 cm^-1 and 1505—1499 cm^-1 are the characteristic absorption bands for vc=O and vc=N. In the IH NMR spectra of target compounds(10a—10g), three protons of a = CH—CH2— group present three sets of quartet peaks of the protons. The preliminary bioassays showed that the synthesized compounds exhibited some activities of fungicides and plant growth regulators.     

SYNTHESES AND CRYSTAL STRUCTURES OF (Et_4N)_2(Fe_2Se_2(SPh)_4) AND (Et_4N)_2(Fe_4Se_4Cl_4)

<正> Since the discovery of iron-sulfur proteins , a number of analogous compounds of the active sites of iron-sulfur proteins has been synthesized and characterized . Due to the similarity between sulfur and selenium, some selenoproteins with similar active site as iron-sulfur proteins were found . We have synthesized a series of iron-selenium compounds in correlative study with the iron-sulfur compounds. In this paper, we will discuss the syntheses and crystal stuctures of the title compounds. The spectroscopic properties of these compounds have been under investigation.     

Synthesis of N-arylquinolone derivatives bearing 2-thiophenoxyquinolines and their antimicrobial evaluation

A new series of 2-thiophenoxyquinolines based trifluoromethyl substituted N-aryl quinolone derivatives8a–f and 9a–f have been synthesized via a one-pot multicomponent reaction. In vitro antimicrobial activity of the synthesized compounds was investigated against a representative panel of pathogenic strains. Compounds 8c, 9c and 9e exhibited comparable antimicrobial activity to first line drugs.     

Synthesis and activities of new 4-hydroxy benzoxazolone derivatives

<正>A series of new 4-substituted benzoxazolone derivatives were synthesized according to a convenient method,their anti-inflammatory and analgesic activities in vivo were evaluated.All of them were new compounds,the structures of all the synthesized compounds were confirmed by ~1H NMR,~(13)C NMR,ESI-MS and HR-MS.Most of the compounds exhibited anti-inflammatory activity.     

Design, synthesis, and screen of cathepsin K inhibitors

We synthesized a series of epoxysuccinic acid derivatives and evaluated their in vitro cathepsin K inhibitory activity The screening results show that the potency of compounds 9e,9d,9p,9j and 9k (IC₅₀≤0.005μmol/L) were equal to or greater than that of the lead compound 9a.Less hydrophobic compounds showed weaker potency,which can be explained by the hydrophobic nature of the cathepsin K binding pockets.     

On the Rational Drug Design for Hypertension through NMR Spectroscopy

Antagonists of the AT1receptor (AT1R) are beneficial molecules that can prevent the peptide hormone angiotensin II from binding and activating the specific receptor causing hypertension in pathological states. This review article summarizes the multifaced applications of solid and liquid state high resolution nuclear magnetic resonance (NMR) spectroscopy in antihypertensive commercial drugs that act as AT1R antagonists. The 3D architecture of these compounds is explored through 2D NOESY spectroscopy and their interactions with micelles and lipid bilayers are described using solid state ¹³CP/MAS, ³¹P and ²H static solid state NMR spectroscopy. Due to their hydrophobic character, AT1R antagonists do not exert their optimum profile on the AT1R. Therefore, various vehicles are explored so as to effectively deliver these molecules to the site of action and to enhance their pharmaceutical efficacy. Cyclodextrins and polymers comprise successful examples of effective drug delivery vehicles, widely used for the delivery of hydrophobic drugs to the active site of the receptor. High resolution NMR spectroscopy provides valuable information on the physical-chemical forces that govern these drug:vehicle interactions, knowledge required to get a deeper understanding on the stability of the formed complexes and therefore the appropriateness and usefulness of the drug delivery system. In addition, it provides valuable information on the rational design towards the synthesis of more stable and efficient drug formulations.     

Application of Validated TLC—Densitometric Method for Simultaneous Identification and Determination of Losartan Potassium,Telmisartan, and Valsartan in Tablets

JPC – Journal of Planar Chromatography – Modern TLC - The antihypertensive effect of sartans is a result of inhibition of the binding of angiotensin (AT) II to the AT1 receptor in...     

Synthesis and antiallergy activity of [1,3,4]thiadiazolo[3,2-a]-1,2,3-triazolo[4,5-d]pyrimidin-9(3H)-one derivatives. II. 6-Alkyl- and 6-cycloalkylalkyl derivatives.

A series of 6-alkyl- or 6-(cycloalkylalkyl)-[1,3,4]thiadiazolo[3,2- a]-1,2,3-triazolo[4,5-d]pyrimidin-9(3H)-ones 1b--o was synthesized from the corresponding 1,3,4-thiadiazol-5-amines 3b--o and the antiallergic activities of the products were evaluated. Among the compounds 6-(2-cyclohexylethyl)- [1,3,4]thiadiazolo[3,2-a]-1,2,3-triazolo[4,5-d]pyrimidin-9(3H)-one 1h, whose X-ray crystallographic stereostructure is shown, was found to be a promising new antiallergic agent, which has low toxicity and dual activity as a leukotriene D4 receptor antagonist and as an orally active mast cell stabilizer.     

Synthesis and Evaluation of Some New (1,2,4) Triazolo(4,3‐a)Quinoxalin‐4(5H)‐one Derivatives as AMPA Receptor Antagonists

This study involves the synthesis and anticonvulsant evaluation of 1‐ethyl‐3‐hydrazinylquinoxaline‐2‐(1H)‐one ( 8 ), its chemical confirmations 9 and 10 and certain (1,2,4) triazolo(4,3‐a)quinoxalin‐4(5H)‐one compounds 11 , 12 , 13 , 13a , 13b , 13c , 13d , 13e , 13f , 14 , 15 , 16 . The structure of the synthesized compounds was confirmed chemically by elemental analyses and spectral data (IR, ¹H NMR, ¹³C NMR, and Mass). Docking studies were preformed to all of the synthesized compounds to predict, in a qualitative way, the anticonvulsant activity of the proposed compounds. There is a promising correlation between the results of molecular modeling and the anticonvulsant activity of the synthesized compounds. The highest fitting value was noticed for compounds 9 and 10 , which showed the highest anticonvulsant activity.     

Synthesis of 10‐substituted 3,6‐Diphenyl‐9‐aryl‐3,4,6,7,9,10‐hexahydro‐acridine‐1,8(2H,5H)‐dione Derivatives and Biological Activities

A series of novel 10‐substituted 3,6‐diphenyl‐9‐aryl‐3,4,6,7,9,10‐hexahydroacridine‐1,8(2H,5H)‐dione derivatives 2 were synthesized by condensation of compounds 1 with amines, which the compounds 1 were synthesized by 5‐phenylcyclohexane‐1,3‐dione and aromatic aldehydes according to Knoevenagel, Michael, and cyclization reactions in the presence of a very small amount of l‐proline as catalyzed at room temperature. The structures of all the synthesized compounds were characterized by IR, 1H NMR, and MS. In addition, the molecular structures of compound 1a have been determined by single‐crystal X‐ray diffraction analysis.     

Prediction of COVID-19 manipulation by selective ACE inhibitory compounds of Potentilla reptant root: In silico study and ADMET profile

In the novel SARS-CoV-2 (COVID-19) as a global emergency event, the main reason of the cardiac injury from COVID-19 is angiotensin-converting enzyme 2 (ACE2) targeting in SARS-CoV-2 infection. The inhibition of ACE2 induces an increase in the angiotensin II (Ang II) and the angiotensin II receptor type 1 (AT1R) leading to impaired cardiac function or cardiac inflammatory responses. The ethyl acetate fraction of Potentilla reptans L. root can rescue heart dysfunction, oxidative stress, cardiac arrhythmias and apoptosis. Therefore, isolated components of P. reptans evaluated to identify natural anti-SARS-CoV-2 agents via molecular docking.In silico molecular docking study were carried out using the Auto Dock software on the isolated compounds of Potentilla reptans root. The protein targets of selective ACE and others obtained from Protein Data Bank (PDB). The best binding pose between amino acid residues involved in active site of the targets and compounds was discovered via molecular docking. Furthermore, ADMET properties of the compounds were evaluated.The triterpenoids of P. reptans showed more ACE inhibitory potential than catechin in both domains. They were selective on the nACE domain, especially compound 5. Also, the compound 5 & 6 had the highest binding affinity toward active site of nACE, cACE, AT1R, ACE2, and TNF-α receptors. Meanwhile, compound 3 showed more activity to inhibit TXA2. Drug likeness and ADMET analysis showed that the compounds passed the criteria of drug likeness and Lipinski rules. The current study depicted that P. reptans root showed cardioprotective effect in COVID-19 infection and manipulation of angiotensin II-induced side effects.     

Angiotensin-II Analogues. I: Synthesis and incorporation of the halogenated amino acids 3-(4′-iodophenyl)alanine, 3-(3′,5′-dibromo-4′-chlorophenyl)alanine, 3-(3′,4′,5′-tribromophenyl)alanine,and 3-(2′,3′,4′,5′,6′-pentabromophenyl)alanine

The synthesis of the polyhalogenated phenylalanines Phe(3′,4′,5′-Br₃) ( 3 ), Phe(3′,5′-Br₂-4′-Cl) ( 4 ) and DL -Phe (2′,3′,4′,5′,6′-Br₅) ( 9 ) is described. The trihalogenated phenylalanines 3 and 4 are obtained stereospecifically from Phe(4′-NH₂) by electrophilic bromination followed by Sandmeyer reaction. The most hydrophobic amino acid 9 is synthesized from pentabromobenzyl bromide and a glycine analogue by phase-transfer catalysis. With the amino acids 4, 9 , Phe(4′-I) and D -Phe, analogues of [1-sarcosin]angiotensin II ([Sar¹]AT) are produced for structure-activity studies and tritium incorporation. The diastereomeric pentabromo peptides L - and D - 13 are separated by HPLC. and identified by catalytic dehalogenation and comparison to [Sar¹]AT ( 10 ) and [Sar¹, D -Phe⁸]AT ( 14 ).     

Novel Therapeutic Effects of Pterosin B on Ang II-Induced Cardiomyocyte Hypertrophy

Pathological cardiac hypertrophy is characterized by an abnormal increase in cardiac muscle mass in the left ventricle, resulting in cardiac dysfunction. Although various therapeutic approaches are being continuously developed for heart failure, several studies have suggested natural compounds as novel potential strategies. Considering relevant compounds, we investigated a new role for Pterosin B for which the potential life-affecting biological and therapeutic effects on cardiomyocyte hypertrophy are not fully known. Thus, we investigated whether Pterosin B can regulate cardiomyocyte hypertrophy induced by angiotensin II (Ang II) using H9c2 cells. The antihypertrophic effect of Pterosin B was evaluated, and the results showed that it reduced hypertrophy-related gene expression, cell size, and protein synthesis. In addition, upon Ang II stimulation, Pterosin B attenuated the activation and expression of major receptors, Ang II type 1 receptor and a receptor for advanced glycation end products, by inhibiting the phosphorylation of PKC-ERK-NF-κB pathway signaling molecules. In addition, Pterosin B showed the ability to reduce excessive intracellular reactive oxygen species, critical mediators for cardiac hypertrophy upon Ang II exposure, by regulating the expression levels of NAD(P)H oxidase 2/4. Our results demonstrate the protective role of Pterosin B in cardiomyocyte hypertrophy, suggesting it is a potential therapeutic candidate.     

Synthesis of thiourea derivatives as CCR4 antagonists

A series of thiourea derivatives have been synthesized. Their structures were confirmed by MS and 1H NMR. Several compounds showed potent activities as antagonists of CCR4 receptor.     

Crosslinking photosensitized by a ruthenium chelate as a tool for labeling and topographical studies of G-protein-coupled receptors

The purpose was to apply oxidative crosslinking reactions to the study of recognition and signaling mechanisms associated to G-protein-coupled receptors. Using a ruthenium chelate, Ru(bipy)(3)(2+), as photosensitizer and visible light irradiation, in the presence of ammonium persulfate, we performed fast and efficient covalent labeling of the B(2) bradykinin receptor by agonist or antagonist ligands possessing a radio-iodinated phenol moiety. The chemical and topographical specificities of these crosslinking experiments were investigated. The strategy could also be applied to the covalent labeling of the B(1) bradykinin receptor, the AT(1) angiotensin II receptor, the V(1a) vasopressin receptor and the oxytocin receptor. Interestingly, we demonstrated the possibility to covalently label the AT(1) and B(2) receptors with functionalized ligands. The potential applications of metal-chelate chemistry to receptor structural and signaling studies through intramolecular or intermolecular crosslinking are presented.