Synthesis and antibacterial activity of new N-[2-(thiophen-3-yl)ethyl] piperazinyl quinolones

As a part of continuing search for potential antibacterial agents in the quinolones field, we have synthesized novel quinolone agents bearing N-[2-(thiophen-3-yl)ethyl] piperazinyl moiety in the 7-position of the quinolone ring. In vitro antibacterial evaluation of the target compounds showed that N-[2-(thiophen-3-yl)ethyl] group attached to piperazine ring served as promising C-7 substituent for piperazinyl quinolone antibacterials. Among these derivatives, ciprofloxacin analogues, containing N-[2-(thiophen-3-yl)-2-hydroxyiminoethyl] or N-[2-(thiophen-3-yl)-2-methoxyiminoethyl] residue provided a high inhibition against all the tested Gram-positive organisms including methicillin-resistant Staphylococcus aureus comparable or superior with respect to the reference drugs norfloxacin and ciprofloxacin.     

Synthesis and antibacterial activity of N-[2-(2-naphthyl)ethyl]piperazinyl quinolones

A series of N-[2-(2-naphthyl)ethyl]piperazinyl quinolones containing a carbonyl related functional groups (oxo- or oxyimino-) on the ethyl spacer was synthesized and evaluated for antibacterial activity. The synthesis of N-[2-(2-naphthyl)ethyl]piperazinyl quinolones was achieved through the versatile and efficient synthetic route that involved reaction of piperazinyl quinolones with appropriate α-bromoketone or α-bromooxime derivatives. The structures of new compounds were confirmed by elemental analysis, IR and NMR spectra. Antibacterial data indicated that some of the new N-[2-(2-naphthyl)ethyl]piperazinyl quinolones showed good antibacterial activity and modification of the position 8 and N-1 substituent on quinolone ring, and ethyl spacer functionality produced significant changes in activity against Gram-positive and Gram-negative bacteria.     

Palladium-catalyzed [3 + 2] cycloaddition reaction using 2-(sulfonylmethyl)- or 2-(cyanomethyl)allyl carbonate

Reaction of ethyl 2-(sulfonylmethyl)- or 2-(cyanomethyl)allyl carbonate with α,β-unsaturated esters or ketones in the presence of PD₂(dba)₃·.CHCl₃-dppe catalyst gave highly functionalized cyclopentanes regio-selectively in good yields.     

The synthesis of 7-(substituted-amino)-3-azabicyclo[3.2.0] heptanes

1,2-Cycloaddition reactions of several enamines with N-substituted maleimides and 4-phenyl-1,2,4-triazoline-3,5-dione have been carried out. The adducts were transformed into 7-(substituted-amino)-3-azabicyclo[3.2.0]heptanes and a 1,2,4-triazolidine-1-acetaldehyde, respectively. These are the first reported examples of 3-azabicyclo[3.2.0]heptanes substituted in any position other than the 3-position. The reaction of an ynamine with N-benzylmaleimide afforded a bicyclic intermediate which upon hydrolysis gave a 2,5-dioxo-3-pyrrolidineacetic acid.     

Synthesis and biological activity of new 2-amino-4-[3-methyl-3-(5,6,7,8-tetrahydro-2-naphthyl)cyclobutyl]thiazole derivatives

2-Amino-4-[3-methyl-3-(5,6,7,8-tetrahydro-2-naphthyl)cyclobutyl]thiazole was synthesized by reaction of 1-methyl-1-(5,6,7,8-tetrahydro-2-naphthyl)-3-chloroacetylcyclobutane with thiourea in ethanol, and its subsequent transformations afforded new derivatives which were tested in vitro for antibacterial activity against some bacteria using the disk diffusion technique.__________From Zhurnal Organicheskoi Khimii, Vol. 40, No. 12, 2004, pp. 1861–1865.Original English Text Copyright © 2004 by Koparr, Cansz, Ahmedzade.The original article was submitted in English.     

Design, synthesis and antiinflammatory activity of a new indomethacin ester. 2-[N-[3-(3-(piperidinomethyl)phenoxy)propyl]carbamoylmethylthio]ethyl 1-(p-chlorobenzoyl)-5-methoxy-2-methyl-indole-3-acetate

A novel indomethacin ester prodrug, 2-[N-[3-(3-(piperidinomethyl)phenoxy)propyl]carbamoylmethylthio ]ethyl 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetate (1) was prepared from a new histamine H2-receptor antagonist, N-[3-(3-(piperidinomethyl)phenoxy)propyl]-2-(2-hydroxyethylthio )acetamide (2) and indomethacin (3). The compound 1 was shown to be essentially similar to 3 in its antiinflammatory action and to almost completely inhibit carrageenin-induced hind-paw edema in the rat at a very high dose of 230 mg/kg (280 mumol/kg), which is comparable to that of 100 mg/kg (280 mumol/kg) of 3, without producing gastric lesions. On a molar basis, the acute gastric lesioning properties of 1 were near one-hundred times less than those of 3, resulting in over a twenty-fold improvement in the ratio of antiedema activity to ulcerogenicity. The effect of the co-administration of histamine H2-receptor antagonists on antiedema activity and ulcerogenicity caused by 3 is also discussed.     

Preparation of 2(3)-O-[2-(hydroxyamino)-2-oxoethyl]- and 2(3)-O-[3-(hydroxyamino)-3-oxopropyl]dextran

Hydroxame derivatives of carboxymethyl- and carboxyethyldextrans have been prepared and characterized by elemental analysis as well as by IR and UV spectroscopy. The effect of reaction conditions on the products yield has been studied.     

Synthesis and biological activity of new 2-[(3-aminopropyl)dimethyl-silyl]-5-trialkylgermylfurans

New highly cytotoxic 3-aminopropyl derivatives of 2-dimethylsilyl-5-trialkylgermylfuran (IC₅₀ 1−3 μg⋅ml⁻¹) have been prepared by hydrosilylation of heterocyclic N-allylamines with the corresponding hydrosilane in the presence of Speier’s catalyst. The influence of the amine structure and alkyl substituent at the germanium atom on the cytotoxicity has been investigated.     

Synthesis and in vitro biological activity of some 7-[hydrazino], -[hydrazonyl] and -[pyrazolyl]quinolone-3-carboxylic acids

1-Ethyl-6-fluoro-7-hydrazino-1,4-dihydro-4-oxoquinoline-3-carboxylic acid ( 8 ) has been prepared and served as a versatile intermediate from which a number of hydrazone, pyrazole and dihydropyridazine derivatives were synthesized. The in vitro biological activity of some of these derivatives is reported.     

Novel non-peptide GPIIb/IIIa antagonists: synthesis and biological activities of 2-[4-[2-(4-amidinobenzoylamino)-2-(substituted)acetyl]-3-(2-methoxy-2-oxoethyl)-2-oxopiperazinyl] acetic acids

To improve the in vitro and in vivo potency of our first low molecular weight GPIIb/IIIa antagonist 1 (TAK-029), a series of 2-[4-[2-(4-amidinobenzoylamino)-2-(substituted)acetyl]-3-(2-methoxy-2-oxoethyl)-2-oxopiper-azinyllacetic acids were synthesized through modification of the glycine moiety of 1 and evaluated for their ability to inhibit in vitro adenosine 5'-diphosphate (ADP)-induced platelet aggregation of guinea pig platelet rich plasma (PRP). Among the compounds examined, the (3S,2S)-4-methoxyphenylalanine derivative 4h showed the most potent antagonistic activity with an IC50 value of 13 nM. Dose-dependent inhibition of ex vivo platelet aggregation was achieved with oral administration of 4h (0.3-1.0 mg/kg) to guinea pigs. Complete inhibition was observed for up to 8 h, and 43% inhibition could still be observed 24 h after oral administration of 1.0 mg/kg. The long-lasting antiplatelet effect of 4h suggests that 4h would be suitable for once-a-day dosing. Structure-activity relationships (SAR) were examined in the series of the phenylalanine derivatives. An increase in the electron density around the 4-position of the phenyl ring of the phenylalanine moiety led to an increase in the antiplatelet activity, suggesting the existence of a hydrophobic and electrostatic interaction site in addition to the ionic binding sites in the GPIIb/IIIa.     

4-(硝基苯基)-3-硫代脲酸烷基酯类的合成及其生物活性研究

通过硝基苯胺同烷氧酰基异硫氰酸酯的化合反应以及钛酸丁酯的酯交换反应共合成了9个4-(硝基苯基)-3-硫代脲酸烷基酯类化合物(1-9)。通过各种波谱分析确定了它们的化学结构, 并研究了这类物质对农杆菌的抑制作用。     

Microwave-assisted synthesis and biological activity of new Schiff bases derived from dimers of 4-amino-3-[3-(1-benzyl)indole]-5-thiomethyl-1,2,4-triazole

An expeditious method with microwave irradiation has been developed for synthesis of novel Schiff bases from dimers of 4-amino-3-[3-(1-benzyl)indole]-5-thiomethyl-1,2,4-triazole. Its distinct advantages are short reaction times and good conversion. The structures of these new Schiff bases were established by ¹H NMR, IR, and mass spectroscopy, and elemental analysis. The antibacterial activity of ten novel Schiff bases against three bacterial strains was studied by the disk diffusion method. Preliminary results indicated that some of the compounds had strong antibacterial activity.     

2-[3-(Trifluoromethyl)phenyl]furo[3,2-b]pyrroles: synthesis and reactions

The synthesis and reactions of methyl 2-[3-(trifluoromethyl)phenyl]-4H-furo[3,2-b]pyrrole-5-carboxylate (1a) are described. Upon reaction with methyl iodide, benzyl chloride, or acetic anhydride, this compound gave N-substituted products 1b-d. By hydrolysis of compounds 1a-c, the corresponding acids 2a-c were formed, or by reaction with hydrazine-hydrate, the corresponding carbohydrazides 3a-c were formed. By heating 2-[3-(trifluoromethyl)phenly]-4H-furo[3,2-b]pyrrole-5-carboxylic acid (2a) in acetic anhydride, 4-acetyl-2-[3-(trifluoromethyl)phenyl]furo[3,2-b]pyrrole (4) was formed. By hydrolysis of 4, 2-[3-(trifluoromethyl)phenyl]-4H-furo[3,2-b]pyrrole (5a) was formed, and reactions with methyl iodide or benzyl chloride gave N-substituted products 5b-c. The reaction of 4 with dimethyl butynedioate gave substituted benzo[b]furan 6. Compound 3a reacted with triethyl orthoesters giving 7a-c, which afforded with phosphorus (V) sulphide the corresponding thiones 8a-c. The thiones 8a-c reacted with hydrazine hydrate to form hydrazine derivatives 9a-c. The reaction of triethyl orthoformiate with compounds 9a-c led to furo[2′,3′: 4,5]pyrrolo[1,2-d][1,2,4]triazolo[3,4-f][1,2,4]triazines 10a-c. Hydrazones 11a-c were formed from 3a-c and 5-[3-(trifluoromethyl)phenyl]furan-2-carboxaldehyde. The effect of microwave irradiation on some condensation reactions was compared with “classical” conditions. The results showed that microwave irradiation shortens the reaction time while affording comparable yields.     

One-step synthesis of the tricyclic core of martinellic acid from 2-(cyanomethyl)-3-oxo-N-arylbutanamides

A SnCl4.5H2O-mediated facile and efficient one-step synthesis of the tricyclic core of martinellic acid from readily available 2-(cyanomethyl)-3-oxo-N-arylbutanamides was developed and a mechanism involving consecutive hydrolysis of a cyano group and a double annulation process is proposed.     

Iron-mediated [3 + 2] or [3 + 3] annulation of 2-(2-(ethynyl)phenoxy)-1-arylethanones: selective synthesis of indeno[1,2-c]chromenes and 5H-naphtho[1,2-c]chromenes

An iron-mediated tandem annulation strategy has been developed for the synthesis of numerous functional indeno[1,2-c]chromenes and 5H-naphtho[1,2-c]chromenes. This work is the first to disclose an iron-mediated method through sequential electrophilic addition of a ketone to an alkyne and annulation tandem reaction. Importantly, a halide is introduced into the products by a ring-opening process among the annulation of alkynylcyclopropanes, which makes the methodology more attractive for organic synthesis.