Synthesis of new oxazolidine,oxazolidin-2-one and perhydro-1,4-oxazine derivatives of arylethanolamine as potential beta3-adrenoceptor agonists

The synthesis of new cyclic compounds, arylethanolamine derivatives, with potential beta₃-adrenoceptor agonist selectivity, which are associated with thermogenesis and regulation of insulin release, are described. Oxazolidine, oxazolidin-2-one, and perhydro-1,4-oxazine derivatives were obtained. The preliminary evaluation of the pharmacological effects of some of the synthesized compounds showed an activation of lypolysis in rat adipocytes with potency and efficiency similar to that observed for other accredited beta₃-adrenergic agonists.     

A synthesis of 5-amino- and 5-hydroxy-l-ethyl-1,4-dihydrio-4-oxo-3-quinolinecarboxylic acids and their derivatives

The synthesis and antimicrobial activity of 5-Hydroxy-l-ethyl-1,4-dihydrio-4-oxo-3-quinolinecarboxylic acids and their derivatives have been investigated. The 5-hydroxy-3-quinolinecarboxylic acids were prepared by thermal cyclization of 3-oxocyclohexenylaminomethylenemalonates followed by aromatiza-tion with iodine-ethanol, ethylation and hydrolysis of products. The 5-amino derivatives were prepared by several steps involving novel aromatization of isoxazole intermediates.     

The synthesis of a series of 7-amino-1-cyclopropyl-8-fluoro-1,4-dihydro-4-oxo-1,6-naphthyridine-3-carboxylic acids as potential antibacterial agents

A series of 7-amino-1-cyclopropyl-1,4-dihydro-8-fluoro-4-oxo-1,6-naphthyridine-3-carboxylic acids has been prepared and evaluated for antibacterial activity. These compounds were prepared by the displacement of the chloro substituent from 7-chloro-1-cyclopropyl-1,4-dihydro-8-fluoro-4-oxo-1,6-naphthyridine-3-carboxylic acid employing the requisite nitrogen nucleophile to produce the title compounds. The naphthyridine acid was synthesized in ten steps from ethyl 2,4-dihydroxy-3-nitro-5-pyridinecarboxylate. The key step in the sequence was a Schiemann reaction carried out using the hexafluorophosphate salt of the diazonium ion derived from ethyl 3-amino-2,4-dichloro-5-pyridinecarboxylate.     

Studies on chemotherapeutics III. Synthesis and cyclisation of 5-substituted-4-oxo-1,4-dihydro-3-pyridinecarbonyl-semicarbazide and- thiosemicarbazide

1,4-Disubstituted-semicarbazide and thiosemicarbazide derivatives were synthetized from 5-substituted-4-oxo-1,4-dihydro-3-pyridinecarbohydrazides and cyclized to 3-mercapto-4H-1,2,4-triazoles. The obtained compounds could be S-methylated with methyl iodide in methanol. The new compounds were tested for antibacterial and antifungal activities.     

Study of physicochemical properties-antitubercular activity relationship of naphthalene-1,4-dione analogs: A QSAR approach

Enduring pandemic nature of tuberculosis urges to explore novel antimycobacterial agents with different mechanism of actions. Plant containing 1,4-naphthoquinone derivatives showed promising antitubercular activity with novel mode of action and their synthetic/semi-synthetic derivatives devoid of toxicity. Structural requirements of naphthalene-1,4-dione derivatives towards antitubercular activity and cytotoxicity were explored using a mathematical model in order to understand their physicochemical parameters. A quantitative structure activity relationship study furnished some important structural insights for antitubercular activity, i.e. average connectivity index, information content index of neighborhood symmetry, aromatic ratio, and path/walk 3 Randic shape index. Similarly it also provides drivers for the cytotoxicity of compounds. These drivers will be helpful in further development of safer and potent 1,4-naphthoquinone derivatives.     

1,4-bis(3-aminopropyl)piperazine libraries: from the discovery of classical chloroquine-like antimalarials to the identification of new targets

The purpose of this review is to provide an update on our work based on the 1,4-bis(3-aminopropyl)piperazine skeleton and how it allowed our group to validate a new target. After a brief introduction where we will relate the way this substructure was introduced in our 4-aminoquinolinyl derivatives, we will present first the different libraries synthesized around this moiety: (1) libraries of sulfonamides, amides and amines derived from 4-aminoquinolines and, (2) libraries where the 4-aminoquinoline nucleus is replaced. High throughput evaluation of biological activity and physicochemical parameters will be presented. The evaluation of the anti-malarial activity of the compounds will be discussed in the light of a chloroquine-like mechanism (accumulation in the acidic food vacuole and inhibition of beta-hematin formation). In a second part we will present active 1,4-bis(3-aminopropyl)piperazine as tools for identification and/or validation of new antimalarial targets. Fluorescence assays on some derivatives show that they are surprisingly localized outside the food vacuole, suggesting the existence of other target(s). Secondly, we will present a library of 1,4-bis(3-aminopropyl)piperazine as inhibitors of the cytosolic aminopeptidase Pfa-M1, a new potential target for antimalarials.     

Synthesis of 5-aryl-2-oxopyrrole derivatives as synthons for highly substituted pyrroles

A small library of 2-oxo-5-(hetero)arylpyrroles was prepared starting from 2,3-dioxo-5-(hetero)arylpyrrolidines. The large synthetic possibilities of these 2-oxopyrroles were investigated. The 2-oxopyrroles offer a large number of possible derivatizations including reactions with electrophiles. The chloroformylation of 2-oxo-5-(hetero)arylpyrroles provides pyrrole carbaldehydes. Some pyrrole carbaldehydes were used to synthesize polycyclic compounds like pyrrolo[3,4-d]pyridazinones, a thienopyrrole, a pyrrolobenz[1,4]oxazepine, a pyrrolobenzo[1,4]thiazepine, and a pyrrolobenzo[1,4]diazepine. Hereby we showed through a short exploration that the oxopyrroles and analogues are interesting and versatile synthetic building blocks.     

New 7-substituted quinolone antibacterial agents. II. The synthesis of 1-ethyl-1,4-dihydro-4-oxo-7-(pyrazolyl,isoxazolyl, and pyrimidinyl)-1,8-naphthyridine and quinolone-3-carboxylic acids

Synthetic methods for the construction of certain aromatic heterocyclic side chains for the quinolone anti-bacterials have been provided. In particular a series of 7-(pyrazol-3 or 4-yl, 4- or 5-isoxazolyl and 4- or 5-pyrimidinyl)-1-ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine and quinoline-3-carboxylic acids have been prepared. All of the heterocycles were prepared from masked 1,3-dicarbonyl derivatives of nalidixic acid ( 9,17 ) or 7-acetyl-1-ethyl-1,4-dihydro-4-oxo-3-quinoline carboxylic acids ( 8 ). These masked 1,3-dicarbonyl derivatives were prepared by the use of t-butoxy-bis-dimethylaminomethane on the activated methyls of 9,19 and 8 . The pyrimidinyl analogs, substituted with a 2-amino or a 2-aminomethyl moiety, were the only derivatives with substantial antibacterial activity.     

Synthesis and reactions of 7-fluoro-4-methyl-6-nitro-2-oxo-2H-1-benzopyran-3-carboxylic acid: a novel scaffold for combinatorial synthesis of coumarins

7-Fluoro-4-methyl-6-nitro-2-oxo-2H-1-benzopyran-3-carboxylic acid has been prepared as a novel scaffold for combinatorial synthesis of coumarins. The scaffold has three points of diversity. The optimal conditions for its reactions with different nucleophiles in solid phase were obtained. Sixteen coumarin derivatives with different structures were designed and synthesized in solid phase to demonstrate its application as a scaffold for combinatorial synthesis of coumarins. Thirteen of these derivatives were obtained in high yields. Many of these model compounds fluoresce. Combinatorial libraries constructed with this novel scaffold may have interesting biological or physical properties.     

Synthesis of 1,4-benzothiazin-2-yl derivatives of 1,3-dicarbonyl compounds and benzothiazinone spiro derivatives by the reaction of 2-chloro-1,4-benzothiazin-3-ones with ‘push-pull’ enamines

The reaction of 2-chloro-3-oxo-3,4-dihydro-2H-1,4-benzothiazines with ‘push-pull’ enamines was investigated. The reaction with the enamines occurs at the β-carbon atom in the presence of a small excess of triethylamine. As a result, a set of 3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl derivatives of 1,3-dicarbonyl compounds and benzothiazinone spiro derivatives was prepared. On acidic hydrolysis of ethyl 2-ethyl-3-(methylimino)-2-(3-oxo-3,4-dihydro-2H-1,4-benzothiazin-2-yl)butanoate, a new rearrangement affording ethyl 11-ethyl-2,3-dimethyl-4-oxo-2,3,4,5-tetrahydro-1H-2,5-methano-6,1,3-benzothiadiazocine-11-carboxylate was discovered. A plausible mechanism and factors influencing the course of the reaction are discussed.     

系列C3α-位芳基取代的四氢吡咯并吲哚骨架衍生物的合成

通过银促进的傅-克反应可以合成系列C3α-位为不同类型芳基取代的四氢吡咯并吲哚骨架的类天然产物.在该合成方法的基础上,发现C3α-位分别为对乙酰氨基苯基取代和甲基吲哚取代的四氢吡咯并吲哚类衍生物3a和3b对多种肿瘤细胞均表现出微摩尔级的活性,是具有重要临床应用前景的药物候选化合物.为了进一步研究该类化合物的成药性及其构效关系,以化合物3a为前体化合物合成了一系列类天然产物(化合物4～17),对其抗肿瘤活性进行了研究,并初步探讨了其构效关系.所合成化合物的结构经1H NMR、13C NMR和HRMS分析确证.本研究为该类化合物的临床前研究奠定了基础.     

Studies on the chemistry of 2-(2-oxo-3-phenylpropyl)-benzaldehydes: novel total synthesis of 3-phenylnaphthalen-2-ols and 2-hydroxy-3-phenyl-1,4-naphthoquinones

We describe the first studies on the chemistry of 2-(2-oxo-3-phenylpropyl)benzaldehydes, which were converted into 3-benzylisochromen-1-ones via the corresponding 2-(2-oxo-3-phenylpropyl)benzoic acid. The 2-(2-oxo-3-phenylpropyl)benzaldehydes proved to be convenient starting materials for the synthesis of 3-phenyl-2-naphthols. Oxidation of the latter compounds resulted in a novel, efficient synthesis of 3-phenyl-1,2-naphthoquinones, which were efficiently transformed into 2-hydroxy-3-phenyl-1,4-naphthoquinones.     

Reactions of 5-oxo-1-phenylpyrrolidine-3-carbohydrazides with 1,4-naphthoquinone derivatives and the properties of the obtained products

N′-(4-Oxo-1,4-dihydronaphthalen-1-ylidene)-1-phenyl-5-oxopyrrolidine-3-carbohydrazides and N′-(3-methyl-4-oxo-1,4-dihydronaphthalen-1-ylidene)-1-phenyl-5-oxopyrrolidine-3-carbohydrazides were synthesized by reactions of 5-oxo-1-phenylpyrrolidine-3-carbohydrazides with 1,4-naphthoquinone or 2-methyl-1,4-naphthoquinone. The alkylated analogues of the above products were obtained using ethyl iodide. The interaction of 5-oxo-1-phenylpyrrolidine-3-carbohydrazides with 2,3-dichloro-1,4-naphthoquinone was followed by formation of N′-(3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-1-phenyl-5-oxopyrrolidine-3-carbohydrazides. All these compounds were characterized using ¹H, ¹³C NMR, IR and mass spectra. Some of the new compounds were tested for the antimicrobial and antifungal activity.     

Chemoselective synthesis and cytotoxic activity of a series of novel benzo[1,4]oxazin-3-one derivatives

That tetraacetonitrile copper perchlorate catalyzes intramolecular amidation of arenes was found to be a new strategy for construction of nitrogen-containing heterocycles and resulted in the formation of a series of novel benzo[1,4]oxazin-3-one derivatives from N-(1,3-diphenyl-1H-1,2,4-triazol-5-yl)-2-phenoxyacetamides.This approach of heterocyclic construction proceeds in a chemoselective manner in which only benzo[1,4]oxazin-3-one derivatives were obtained by C—N bonds formation with cheap and simple copper salt catalyst under mild conditions in moderate to good yields.The biological assay of some of benzo[1,4]oxazin-3-one derivatives showed that they had moderate antiproliferative activity toward MDA-MB231 and HeLa cancer cell lines.     

CoMFA and CoMSIA 3D-quantitative structure-activity relationship model on benzodiazepine derivatives, inhibitors of phosphodiesterase IV

Recently, we reported structurally novel PDE4 inhibitors based on 1,4-benzodiazepine derivatives. The main interest in developing bezodiazepine-based PDE4 inhibitors is in their lack of adverse effects of emesis with respect to rolipram-like compounds. A large effort has thus been made toward the structural optimization of this series. In the absence of structural information on the inhibitor binding mode into the PDE4 active site, 2D-QSAR (H-QSAR) and two 3D-QSAR (CoMFA and CoMSIA) methods were applied to improve our understanding of the molecular mechanism controlling the PDE4 affinity of the benzodiazepine derivatives. As expected, the CoMSIA 3D contour maps have provided more information on the benzodiazepine interaction mode with the PDE4 active site whereas CoMFA has built the best tool for activity prediction. The 2D pharmacophoric model derived from CoMSIA fields is consistent with the crystal structure of the PDE4 active site reported recently. The combination of the 2D and 3D-QSAR models was used not only to predict new compounds from the structural optimization process, but also to screen a large library of bezodiazepine derivatives.     

Preparation of Synthetic and Natural Derivatives of Flavonoids Using Suzuki–Miyaura Cross-Coupling Reaction

Herein, we report the use of the Suzuki–Miyaura cross-coupling reaction for the preparation of a library of synthetic derivatives of flavonoids for biological activity assays. We have investigated the reactivity of halogenated flavonoids with aryl boronates and with boronyl flavonoids. This reaction was used to prepare new synthetic derivatives of flavonoids substituted at C-8 with aryl, heteroaryl, alkyl, and boronate substituents. The formation of flavonoid boronate enabled a cross-coupling reaction with halogenated flavones yielding biflavonoids connected at C-8. This method was used for the preparation of natural compounds including C-8 prenylated compounds, such as sinoflavonoid NB. Flavonoid boronates were used for the preparation of rare C-8 hydroxyflavonoids (natural flavonoids gossypetin and hypolaetin). A series of previously unknown derivatives of quercetin and luteolin were prepared and fully characterized.     

Studies on antiulcer drugs. I. Synthesis and antiulcer activities of imidazo[1,2-alpha]pyridinyl-2-oxobenzoxazolidines-3-oxo-2H-1,4-benzoxaz ines and related compounds.

A series of imidazo[1,2-alpha]pyridinyl-2-oxobenzoxazolidines (4a-i), -3-oxo-2H-1,4-benzoxazines (5a-q), their thio-analogues (4j-p and 5r-t) and 5,6,7,8-tetrahydroimidazo[1,2-alpha]pyridinyl derivatives (8 and 9) were synthesized and tested for anti-stress ulcer activity in rats. Several compounds were found to be more active than the reference compounds, zolimidine, cimetidine and sucralfate. Among them, compound 4e, 5i and 5l also exhibited potent protective activity against ethanol-induced gastric lesion. The synthesis and structure-activity relationships of these compounds are discussed.     

Quantitative structure-activity relationship study of N-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)guanidines as potent Na/H exchange inhibitors

We have previously reported that N-(4-isopropyl-2,2-dimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-car bonyl)guanidine (4b) methanesulfonate salt (KB-R9032) is a potent and highly water-soluble Na/H exchange inhibitor. In a series of studies on Na/H exchange inhibitors, we designed and synthesized N-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbonyl)guanidines (5) as more potent inhibitors with high water-solubility. The design strategy for 5 was based on a quantitative structure-activity relationship (QSAR) study, involving the proportional relationship between the biological activity and hydrophobicity of the ring structure of compounds 4. As expected, compounds 5 showed more potent activity than 4. It was found by using the QSAR analysis that 5 were about five-fold more potent than 4. The increase in potency of compounds 5 well agreed with our previous QSAR analysis result. The most potent derivative was the methanesulfonate salt 5d of the 4-isopropyl derivative (IC50=0.0091 microM). And in addition to the in vitro study, 5d showed significant protective activity against a rat acute myocardial infraction model.     

Synthesis and evaluation of antitrypanosomal activity of some thiosemicarbazide derivatives of 1-butyl-6-fluoro-7-morpholino-4-oxo-1,4-dihydroquinoline-3-carboxylic acid

The synthesis of thiosemicarbazide of 1-butyl-6-fluoro-7-morpholino-4-oxo-1,4-dihydroquinoline-3-carboxylic acid as well as its heterocyclic derivatives – 1,3,4-thiadiazole and 1,2,4-triazole are described; the modification of proper 1,2,4-triazole derivative by maleimides is also presented. Spectral properties of the prepared compounds and X-ray analysis for the selected compounds were studied. For the compounds antitrypanosomal potential and the toxicity were determined.     

Design, Practical Synthesis, and Biological Evaluation of Novel 6-(Pyrazolylmethyl)-4-quinoline-3-carboxylic Acid Derivatives as HIV-1 Integrase Inhibitors

A series of novel 6-(pyrazolylmethyl)-4-oxo-4H-quinoline-3-carboxylic acid derivatives bearing different substituents on the N-position of quinoline ring were designed and synthesized as potential HIV-1 integrase (IN) inhibitors, based on the structurally related GS-9137 scaffold. The structures of all new compounds were confirmed by ¹H-NMR, ¹³C-NMR and ESI (or HRMS) spectra. Detailed synthetic protocols and the anti-IN activity studies are also presented.