- Facile and efficient syntheses of a series of N-benzyl and N-biphenylmethyl substituted imidazole derivatives based on (E)-urocanic acid, as angiotensin II AT1 receptor blockers
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In the present work, a facile and efficient route for the synthesis of a series of N-substituted imidazole derivatives is described. Docking studies have revealed that N-substituted imidazole derivatives based on (E)-urocanic acid may be potential antihypertensive leads. Therefore, new AT1 receptor blockers bearing either the benzyl or the biphenylmethyl moiety at the N-1 or N-3 position, either the (E)-acrylate or the propanoate fragment and their related acids at the C-4 position as well as a halogen atom at the C-5 position of the imidazole ring, were synthesized. The newly synthesized analogues were evaluated for binding to human AT1 receptor. The biological results showed that this class of molecules possesses moderate or no activity, thus not always confirming high docking scores. Nonetheless, important conclusions can be derived for their molecular basis of their mode of action and help medicinal chemists to design and synthesize more potent ones. An aliphatic group as in losartan seems to be important for enhancing binding affinity and activity.
- Agelis, George,Kelaidonis, Konstantinos,Resvani, Amalia,Kalavrizioti, Dimitra,Androutsou, Maria-Eleni,Plotas, Panagiotis,Vlahakos, Demetrios,Koukoulitsa, Catherine,Tselios, Theodore,Mavromoustakos, Thomas,Matsoukas, John
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Read Online
- Eleuthesides and their analogs: XI. Final stage of the synthesis of sarcodictyin A analog with 14-methylcyclohex-12-ene ring A
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Proceeding from derivatives of levoglucosenone and piperilene Diels–Alder adduct a total chemical synthesis was completed of sarcodictyin A analog possessing a 14-methylcyclohex-12-ene ring А. A practical version was developed of N(τ)-methylation of uroca
- Sharipov,Pershin,Salikhov, Sh. M.,Valeev
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Read Online
- Reactions of urocanic acid (UCA) methyl esters with singlet oxygen and 4-methyl-1,2,4-triazoline-3,5-dione (MTAD)
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Singlet oxygen adds to the imidazole ring of cis- and trans-methyl urocanate (MUC) to yield the corresponding 2,5-endoperoxides, which are modestly stable at low temperature but decompose upon warming to form complex reaction mixtures. MTAD, a singlet oxygen mimic, reacts with cis- and trans-MUC to yield stereospecific [4+2] reaction products involving the olefinic side chain and the C4-C5 double bond of the imidazole ring. trans-MUC forms a 1:2 MTAD adduct while the cis isomer yields only the 1:1 adduct at 25 °C.?The stereospecificity and absence of MeOH trapping adducts indicate that these reactions may not involve open or trappable dipolar intermediates.
- Roa, Roberto,O'Shea, Kevin E.
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Read Online
- Photoinduced Regioselective Olefination of Arenes at Proximal and Distal Sites
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The Fujiwara-Moritani reaction has had a profound contribution in the emergence of contemporary C-H activation protocols. Despite the applicability of the traditional approach in different fields, the associated reactivity and regioselectivity issues had
- Ali, Wajid,Anjana, S. S.,Bhattacharya, Trisha,Chandrashekar, Hediyala B.,Goswami, Nupur,Guin, Srimanta,Maiti, Debabrata,Panda, Sanjib,Prakash, Gaurav,Saha, Argha,Sasmal, Sheuli,Sinha, Soumya Kumar
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supporting information
p. 1929 - 1940
(2022/02/01)
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- Synthesis and cytotoxicity of novel simplified eleutherobin analogues as potential antitumour agents
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Mixed simplified structures containing the paclitaxel and eleutherobin pharmacophore moieties were analyzed using molecular docking techniques and synthesized based on adamantane and 8-oxabicyclo[3.2.1]octane scaffolds. The crucial role of substituents' stereochemistry in biological activity is discussed. At micromolar concentrations the selected analogues interfered with tubulin dynamics in vitro and in a living organism. Furthermore, new compounds were cytotoxic against human tumour cell lines. The simplified eleutherobin analogues may be considered as prototypes of a new class of antitumour agents.
- Sosonyuk, Sergey E.,Peshich, Anita,Tutushkina, Anastasia V.,Khlevin, Dmitry A.,Lozinskaya, Natalia A.,Gracheva, Yulia A.,Glazunova, Valeria A.,Osolodkin, Dmitry I.,Semenova, Marina N.,Semenov, Victor V.,Palyulin, Vladimir A.,Proskurnina, Marina V.,Shtil, Alexander A.,Zefirov, Nikolay S.
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supporting information
p. 2792 - 2797
(2019/03/12)
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- Discovery of novel propargylamine-modified 4-aminoalkyl imidazole substituted pyrimidinylthiourea derivatives as multifunctional agents for the treatment of Alzheimer's disease
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A series of novel propargylamine-modified pyrimidinylthiourea derivatives (1–3) were designed and synthesized as multifunctional agents for Alzheimer's disease (AD) therapy, and their potential was evaluated through various biological experiments. Among these derivatives, compound 1b displayed good selective inhibitory activity against AChE (vs BuChE, IC50 = 0.324 μM, SI > 123) and MAO-B (vs MAO-A, IC50 = 1.427 μM, SI > 35). Molecular docking study showed that the pyrimidinylthiourea moiety of 1b could bind to the catalytic active site (CAS) of AChE, and the propargylamine moiety interacted directly with the flavin adenine dinucleotide (FAD) of MAO-B. Moreover, 1b demonstrated mild antioxidant ability, good copper chelating property, effective inhibitory activity against Cu2+-induced Aβ1?42 aggregation, moderate neuroprotection, low cytotoxicity, and appropriate blood?brain barrier (BBB) permeability in vitro and was capable of ameliorating scopolamine-induced cognitive impairment in mice. These results indicated that 1b has the potential to be a multifunctional candidate for the treatment of Alzheimer's disease.
- Xu, Yi-xiang,Wang, Huan,Li, Xiao-kang,Dong, Sheng-nan,Liu, Wen-wen,Gong, Qi,Wang, Tian-duan-yi,Tang, Yun,Zhu, Jin,Li, Jian,Zhang, Hai-yan,Mao, Fei
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supporting information
p. 33 - 47
(2017/11/28)
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- NAPHTHYRIDINES AS INHIBITORS OF HPK1
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Naphthyridine compounds and their use as inhibitors of HPK1 are described. The compounds are useful in treating HPK1-dependent disorders and enhancing an immune response. Also described are methods of inhibiting HPK1, methods of treating HPK1-dependent disorders, methods for enhancing an immune response, and methods for preparing the naphthyridine compounds.
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Paragraph 1314; 1315
(2018/10/21)
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- 1,(3,)5-substituted imidazoles, useful in the treatment of hypertension and methods for their preparation
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The present invention provides novel 1,5 and 1,3,5-substituted imidazole compounds in hydrophilic or lipophilic form, which are useful as angiotensin II ATI receptor antagonists suitable for transdermal delivery. The invention also provides pharmaceutical compositions containing such compounds, processes and intermediates for preparing compounds and their use in methods of treating hypertension and cardiovascular diseases.
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Paragraph 0204; 0205; 0210; 0211
(2016/03/04)
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- Synthesis, anti-proliferative activity, and toxicity of C4(C5) substituted N,N′-bis(arylmethyl)imidazolium salts
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The syntheses and characterization of C4and C5substituted N,N′-bis(arylmethyl)imidazolium salts with hydrophilic or lipophilic substituents on the imidazole ring are reported. A structure-activity relationship study revealed that the
- Shelton, Kerri L.,DeBord, Michael A.,Wagers, Patrick O.,Southerland, Marie R.,Taraboletti, Alexandra,Robishaw, Nikki K.,Jackson, Daniel P.,Tosanovic, Radisa,Kofron, William G.,Tessier, Claire A.,Paruchuri, Sailaja,Shriver, Leah P.,Panzner, Matthew J.,Youngs, Wiley J.
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p. 5729 - 5743
(2016/08/30)
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- NRF2 REGULATORS
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The present invention relates to bis aryl analogs, pharmaceutical compositions containing them and their use as Nrf2 regulators.
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Page/Page column 400
(2015/07/07)
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- Thermal 1,3-Trityl migrations in diels-alder domino reactions of 1-Trityl-4-vinyl-1 H-imidazoles
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(Figure presented) Under thermal conditions, tritylimidazoles have been shown to undergo sterically driven N→N trityl migrations, in disagreement with previously published reports. These migrations are a key step in several highly diastereoselective domin
- Cotterill, Lynsey J.,Harrington, Ross W.,Clegg, William,Hall, Michael J.
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supporting information; experimental part
p. 4604 - 4607
(2010/10/02)
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- 2,3,4,5-TETRAHYDRO-1H-1,5-BENZODIAZEPINE DERIVATIVE AND MEDICINAL COMPOSITION
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The present invention has its object to provide a 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine derivative represented with the Formula (1) , or the pharmaceutically acceptable salt, which is effective as a therapeutic and prophylactic agent for diabetes, diabetic nephropathy, or glomerulosclerosis.
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- Inhibitors of protein isoprenyl transferases
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Compounds having the formula or a pharmaceutically acceptable salt thereof wherein R1 is (a) hydrogen, (b) loweralkyl, (c) alkenyl, (d) alkoxy, (e) thioalkoxy, (f) halo, (g) haloalkyl, (h) aryl-L2—, and (i) heterocyclic-L2—; R2 is selected from (a) (b) —C(O)NH—CH(R14)—C(O)OR15, (c) (d) —C(O)NH—CH(R14)—C(O)NHSO2R16 (e) —C(O)NH—CH(R14)-tetrazolyl, (f) —C(O)NH-heterocyclic, and (g) —C(O)NH—CH(R14)—C(O)NR17R18; R3 is heterocyclic, aryl, substituted or unsubstituted cycloalkyl; R4 is hydrogen, lower alkyl, haloalkyl, halogen, aryl, arylakyl, heterocyclic, or (heterocyclic)alkyl; L1 is absent or is selected from (a) —L4—N(R5)—L5—, (b) —L4—O—L5—, (c) —L4—S(O)n—L5— (d) —L4-L6—C(W)—N(R5)—L5—, (e) —L4-L6—S(O)m—N(R5)—L5—, (f) —L4—N(R5)—C(W)—L7-L5—, (g) —L4—N(R5)—S(O)p—L7—L5—, (h) optionally substituted alkylene, (i) optionally substituted alkenylene, and (j) optionally substituted alkynylene are inhibitors of protein isoprenyl transferases. Also disclosed are protein isoprenyl transferase inhibiting compositions and a method of inhibiting protein isoprenyl transferases.
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- Inhibitors of farnesyl-protein transferase
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PCT No. PCT/US97/01354 Sec. 371 Date Jul. 27, 1998 Sec. 102(e) Date Jul. 27, 1998 PCT Filed Jan. 27, 1997 PCT Pub. No. WO97/27852 PCT Pub. Date Aug. 7, 1997The present invention is directed to compounds which inhibit farnesyl -protein transferase (FTase)
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- Characterization of the binding site of the histamine H3 receptor. 1. Various approaches to the synthesis of 2-(1H-imidazol-4-yl)cyclopropylamine and histaminergic activity of (1R,2R)- and (1S,2S)-2-(1H-imidazol-4-yl)- cyclopropylamine
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Various approaches to the synthesis of all four stereoisomers of 2-(1H- imidazol-4-yl)cyclopropylamine (cyclopropylhistamine) are described. The rapid and convenient synthesis and resolution of trans-cyclopropylhistamine is reported. The absolute configur
- De Esch, Iwan J. P.,Vollinga, Roeland C.,Goubitz, Kees,Schenk, Henk,Appelberg, Ulf,Hacksell, Uli,Lemstra, Sylvia,Zuiderveld, Obbe P.,Hoffmann, Marcel,Leurs, Rob,Menge, Wiro M. P. B.,Timmerman, Henk
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p. 1115 - 1122
(2007/10/03)
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- The design of potent, selective, non-covalent, peptide thrombin inhibitors utilizing imidazole as a S1 binding element
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Modeling of neutral or mildly basic functional groups in the S1 site of thrombin led to the targeting of imidazole as a S1 binding element and correctly predicted the optimal chain length for connecting this group with the S2 and S3 binding elements. Deri
- Wiley, Michael R.,Weir, Leonard C.,Briggs, Steven L.,Chirgadze, Nickolay Y.,Clawson, David,Gifford-Moore, Donetta S.,Schacht, Aaron L.,Smith, Gerald F.,Vasudevan, Vasu,Zornes, Larry L.,Klimkowski, Valentine J.
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p. 2767 - 2772
(2007/10/03)
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- INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE
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The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invent
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- trans-4-Methyl-3-imidazoyl pyrrolidine as a potent, highly selective histamine H3 receptor agonist in vivo
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Extensive structural modification of immepyr (+)-2 led to the dsiscovery of trans-4-methyl-3-imidazoyl pyrrolidine (±)-3a as a potent and highly selective H3 agonist. The pyrroline (±)-3a was resolved, and its (+) enantiomer, Sch 50971 [(+)-3a], showed a greater separation of H3 and H1 activities in vivo (H3/H1 ratio >> 330) than (R)-α-methylhistamine (+)-1 (H3/H1 ratio = 17), the standard H3 agonist.
- Shih, Neng-Yang,Aslanian, Robert,Lupo Jr., Andrew T.,Orlando, Steve,Piwinski, John J.,Green, Michael J.,Ganguly, Ashit K.,West, Robert,Tozzi, Salvatore,Kreutner, William,Hey, John A.
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p. 243 - 248
(2007/10/03)
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- 5-membered heterocycles, medicaments containing these compounds, their use and processes for their preparation
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5-Membered heterocyclic compounds, of which the following compounds are exemplary: (a) 4-??trans-4-(2-carboxyethyl)cyclohexyl!aminocarbonyl!-1-(4-piperidyl)imidazole, (b) 5-??trans-4-(2-carboxyethyl)cyclohexyl!aminocarbonyl!-4-methyl-2-(4-piperidyl)-1,3-thiazole, (c) 5-??4-(carboxymethoxy)phenyl!aminocarbonyl!-4-methyl-2-(4-piperidyl)-1,3-thiazole, (d) 5-??trans-4-(2-carboxyethyl)cyclohexyl!aminocarbonyl!-2-(4-piperidyl)-1,3,4-thiadiazole, (e) 5-??4-(carboxymethoxy)phenyl!aminocarbonyl!-2-(4-piperidyl)-1,3,4-thiadiazole, (f) 5-??trans-4-(carboxymethoxy)cyclohexyl!aminocarbonyl!-2-(4-piperidyl)-1,3-thiazole, (g) 5-??4-(carboxymethoxy)phenyl!aminocarbonyl!-2-(4-piperidyl)-1,3-thiazole, (h) 5-??trans-4-(2-carboxyethyl)cyclohexyl!aminocarbonyl!-2-(4-piperidyl)-1,3-thiazole, and (i) 4-??trans-4-carboxycyclohexyl!aminocarbonyl!-1-?2-(4-piperidyl)ethyl!imidazole. These are useful for the treatment or prevention of illnesses in which relatively small or relatively large cell aggregates occur or cell-matrix interactions play a part.
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- New synthetic routes to pyrrolo-[1,2-a]- and -[1,2-c]-imidazol-5-ones by flash vacuum pyrolysis
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1-Substituted and 1,3-disubstituted pyrrolo[1,2-c]imidazol-5-ones 25-27 have been made in fair to excellent yield by flash vacuum pyrolysis (FVP) of the Meldrum's acid precursors 11-13. FVP of the appropriate propenoate precursor 23, 22 and 18-20 gives pyrrolo[1,2-c]imidazol-5-one 2, pyrrolo[1,2-a]-imidazol-5-one 3 and their 6-methyl derivatives 28-30 respectively in 32-90% yield. The mechanism of the propenoate pyrolyses involves rate determining E to Z isomerisation of the alkene followed by elimination of an alcohol and electrocyclisation to the fused ring products.
- McNab, Hamish,Thornley, Craig
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p. 2203 - 2209
(2007/10/03)
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- A Novel Pyrrolidine Analog of Histamine as a Potent, Highly Selective Histamine H3 Receptor Agonist
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Employing classical conformational analysis on a known H3 agonist, (R)-α-methylhistamine (1), a series of conformationally constrained H3 agonists were proposed and synthesized.Pyrrolidine (+/-)-4a, a compound proposed to mimic the a
- Shih, Neng-Yang,Lupo, Andrew T.,Aslanian, Robert,Orlando, Steven,Piwinski, John J.,et al.
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p. 1593 - 1599
(2007/10/02)
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- SELECTIVE N-ALKYLATION OF (E)-UROCANIC ACID
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Various methods of selective alkylation of the N(τ)- and N(?)-nitrogen atoms of the (E)-urocanic acid derivatives are reported.Solid-liquid phase transfer catalysis gave the best results for N(τ)-alkylation of urocanic acid alkyl esters.Liquid-liquid phase transfer catalysis allowed direct N(τ)-akylation of urocanic acid itself.The N(?)-nitrogen atom was alkylated after protection of the N(τ)-nitrogen with a phenacyl group.
- Lauth- Viguerie, Nancy de,Sergueeva, Natalia,Damiot, Monique,Mawlawi, Hiba,Riviere, Monique,Lattes, Armand
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p. 1561 - 1578
(2007/10/02)
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- Five-membered ring systems with bonded imidazolyl ring substituents
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A class of 5-membered heterocyclic compounds having at least one heteroatom, substituted on the heterocyclic ring by an imidazolyl moiety, are useful in the treatment of psychotic disorders (e.g. schizophrenia and mania); anxiety; alcohol or drug withdrawal or dependence; pain; gastric stasis; gastric dysfunction (such as occurs with dyspepsia, peptic ulcer, reflux oesophagitis and flatulence); migraine, nausea and vomiting; movement disorders; and presenile and senile dementia.
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- INFLUENCE OF HYDROGEN BONDING ON THE PROPERTIES OF IRON PORPHYRIN IMIDAZOLE COMPLEXES. AN INTERNALLY HYDROGEN BONDED IMIDAZOLE LIGAND.
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Two new imidazole derivatives have been synthesized, cis-methyl urocanate and trans-methyl urocanate. The IR properties of these imidazole derivatives have been compared with those of imidazole itself and other imidazole derivatives. A series of complexes of the form Fe**I**I**I(TPP)(L)//2SbF//6, where TPP equals tetraphenylporphyrin and L equals imidazole or a substituted imidazole, have been synthesized and characterized by visible, electron paramagnetic resonance and IR spectroscopy and cyclic voltammetry in order to evaluate the effects of hydrogen bonding of coordinated imidazole ligands on the properties of iron porphyrin complexes.
- Quinn,Mercer-Smith,Burstyn,Valentine
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p. 4136 - 4144
(2007/10/02)
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