ChemInform Abstract: SYNTHETIC PENICILLINS, HETEROCYCLIC ANALOGS OF AMPICILLIN, STRUCTURE ACTIVITY RELATIONSHIPS

Hatanaka, Minoru; Ishimaru, Toshiyasu

doi:10.1002/chin.197351413

Cited by 4 publications

(4 citation statements)

References 1 publication

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“…Elemental analyses were performed by our Analytical Laboratory and agreed with theoretical values within ( 0.4%. Besides the commercially available starting materials, 4-hydroxyphenyl glyoxylic acid 60 and 3-thienylglyoxylic acid 61 were prepared in accordance with the reported methods.…”

Section: Methodsmentioning

confidence: 99%

3-Aryl[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-ones: A New Class of Selective A₁ Adenosine Receptor Antagonists

et al. 2001

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Radioligand binding assays using bovine cortical membrane preparations and biochemical in vitro studies revealed that various 3-aryl[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-one (ATBI) derivatives, previously reported by us as ligands of the central benzodiazepine receptor (BzR) (Primofiore, G.; et al. J. Med. Chem. 2000, 43, 96-102), behaved as antagonists at the A1 adenosine receptor (A1AR). Alkylation of the nitrogen at position 10 of the triazinobenzimidazole nucleus conferred selectivity for the A1AR vs the BzR. The most potent ligand of the ATBI series (10-methyl-3-phenyl[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-one 12) displayed a Ki value of 63 nM at the A1AR without binding appreciably to the adenosine A2A and A3 nor to the benzodiazepine receptor. Pharmacophore-based modeling studies in which 12 was compared against a set of well-established A1AR antagonists suggested that three hydrogen bonding sites (HB1 acceptor, HB2 and HB3 donors) and three lipophilic pockets (L1, L2, and L3) might be available to antagonists within the A1AR binding cleft. According to the proposed pharmacophore scheme, the lead compound 12 engages interactions with the HB2 site (via the N2 nitrogen) as well as with the L2 and L3 sites (through the pendant and the fused benzene rings). The results of these studies prompted the replacement of the methyl with more lipophilic groups at the 10-position (to fill the putative L1 lipophilic pocket) as a strategy to improve A1AR affinity. Among the new compounds synthesized and tested, the 3,10-diphenyl[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-one (23) was characterized by a Ki value of 18 nM which represents a 3.5-fold gain of A1AR affinity compared with the lead 12. A rhodopsin-based model of the bovine adenosine A1AR was built to highlight the binding mode of 23 and two well-known A1AR antagonists (III and VII) and to guide future lead optimization projects. In our docking simulations, 23 receives a hydrogen bond (via the N1 nitrogen) from the side chain of Asn247 (corresponding to the HB1 and HB2 sites) and fills the L1, L2, and L3 lipophilic pockets with the 10-phenyl, 3-phenyl, and fused benzene rings, respectively.

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Section: Methodsmentioning

confidence: 99%

3-Aryl[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-ones: A New Class of Selective A₁ Adenosine Receptor Antagonists

et al. 2001

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“…-c,e-h,j,m and 2c,e,g,h,j (Procedure 1). A solution of 2-hydrazinobenzimidazole (3) 19 or 2-hydrazino-1-methylbenzimidazole (4) 19 (4 mmol) and the appropriate glyoxylic acid [36][37][38][39][40] (4.4 mmol) in 10 mL of ethanol was refluxed for 2 h. After cooling, the precipitate which formed was collected to give the substituted (benzimidazol-2-ylhydrazono)acetic acids 5a-c,e-h,j,m and 6c,e,g,h,j, which were purified by suspension in hot methanol (Table 1, Supporting Information). They can be cyclized by means of the following methods.…”

Section: Methodsmentioning

confidence: 99%

3-Aryl-[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-ones: Tricyclic Heteroaromatic Derivatives as a New Class of Benzodiazepine Receptor Ligands

et al. 1999

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A series of 3-substituted [1,2,4]triazino[4,3-c]benzimidazoles V were prepared and tested at the central benzodiazepine receptor (BzR). These compounds were designed as rigid analogues of the previously described N-benzylindolylglyoxylylamide derivatives IV. The title compounds V showed an affinity which depended directly on the presence of the N(10)-H group and an aromatic ring at position 3. Some of them elicited a 2- or 3-fold higher affinity with respect to that of the indolylglyoxylylamide derivatives IV (R = H). The GABA ratio and [(35)S]-tert-butylcyclophosphorothionate binding data revealed an efficacy profile of partial inverse agonists/antagonists for compounds 1c,e,f,j,k, and of a partial agonist for 2c. This last compound proved to be effective in antagonizing pentylenetetrazole-induced seizures in mice. Attempts were made to interpret the structure-affinity relationships of compounds V in the light of possible tautomeric equilibria involving the ligands.

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“…40 This ester was reduced to isothiazole-4-methanol in the manner applied for the homologous 3-methylisothiazole-4-methanol. 41 Methyl oxazole-5-carboxylate 42 was prepared from dimethyl tartrate, via lead tetraacetate oxidation 43 to methyl glyoxylate, and tosylmethyl isocyanide; 44 oxazole-5methanol has been described 45 for use in the synthesis of neooxazolomycin. Ethyl isoxazole-4-carboxylate resulted from oximation of (ethoxycarbonyl)malonaldehyde; 46 isoxazole-4-methanol was obtained by reduction, similar to the homologous tertiary alcohol 47 prepared from this ester and methylmagnesium bromide.…”

Section: Chemistrymentioning

confidence: 99%

Inactivation of O⁶-Alkylguanine-DNA Alkyltransferase. 1. Novel O⁶-(Hetarylmethyl)guanines Having Basic Rings in the Side Chain

et al. 1998

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A number of novel guanine derivatives containing heterocyclic moieties at the O6-position have been synthesized using a purine quaternary salt which reacts with alkoxides under mild conditions. Initially O6-substituents were investigated in which the benzene ring of the known agent, O6-benzylguanine, was replaced by unsubstituted heterocyclic rings. The ability of these agents to inactivate the DNA repair protein O6-alkylguanine-DNA alkyltransferase (ATase), both as pure recombinant protein and in the human lymphoblastoid cell line Raji, has been compared with that of O6-benzylguanine. The present paper focuses on O6-substituents with basic rings, and under standard conditions several of them proved more effective than benzyl for inactivation of both recombinant and Raji ATase. Among the pyridine derivatives, the 2-picolyl compound 7 is not very active in contrast to the 3- and 4-picolyl compounds, and this influenced our choice of isomers of other basic ring systems for study. Since halogen substitution in the thiophene ring considerably increased the activity (17 versus 6), similar modifications in the pyridine series were examined. The more polar O6-substituents in this study are on the whole compatible with the stereochemical requirements of the ATase protein, and their pharmacological properties may be valuable in subsequent in vivo investigations, particularly the thenyl (6), 5-thiazolylmethyl (12), 5-bromothenyl (17), and 2-chloro-4-picolyl (21) derivatives.

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ChemInform Abstract: SYNTHETIC PENICILLINS, HETEROCYCLIC ANALOGS OF AMPICILLIN, STRUCTURE ACTIVITY RELATIONSHIPS

Abstract: Aus den Acetyl‐thiophenen (I) entstehen mit Selendioxid die Ketosäuren (IIa), deren Oxime (IIb) mit Na‐Hg zu den Aminen (III) reduziert werden können.

Cited by 4 publications

References 1 publication

3-Aryl[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-ones: A New Class of Selective A₁ Adenosine Receptor Antagonists

3-Aryl[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-ones: A New Class of Selective A₁ Adenosine Receptor Antagonists

3-Aryl-[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-ones: Tricyclic Heteroaromatic Derivatives as a New Class of Benzodiazepine Receptor Ligands

Inactivation of O⁶-Alkylguanine-DNA Alkyltransferase. 1. Novel O⁶-(Hetarylmethyl)guanines Having Basic Rings in the Side Chain

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ChemInform Abstract: SYNTHETIC PENICILLINS, HETEROCYCLIC ANALOGS OF AMPICILLIN, STRUCTURE ACTIVITY RELATIONSHIPS

Abstract: Aus den Acetyl‐thiophenen (I) entstehen mit Selendioxid die Ketosäuren (IIa), deren Oxime (IIb) mit Na‐Hg zu den Aminen (III) reduziert werden können.

Cited by 4 publications

References 1 publication

3-Aryl[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-ones: A New Class of Selective A1 Adenosine Receptor Antagonists

3-Aryl[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-ones: A New Class of Selective A1 Adenosine Receptor Antagonists

3-Aryl-[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-ones: Tricyclic Heteroaromatic Derivatives as a New Class of Benzodiazepine Receptor Ligands

Inactivation of O6-Alkylguanine-DNA Alkyltransferase. 1. Novel O6-(Hetarylmethyl)guanines Having Basic Rings in the Side Chain

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3-Aryl[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-ones: A New Class of Selective A₁ Adenosine Receptor Antagonists

3-Aryl[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-ones: A New Class of Selective A₁ Adenosine Receptor Antagonists

Inactivation of O⁶-Alkylguanine-DNA Alkyltransferase. 1. Novel O⁶-(Hetarylmethyl)guanines Having Basic Rings in the Side Chain