Synthesis and analgesic activity of 4-aroyl-1<Emphasis Type="Italic">H</Emphasis>-benzo[<Emphasis Type="Italic">c</Emphasis>]oxepin-3-ones

A series of 4-aroyl-1H-benzo[c]oxepin-4-ones have been prepared by heating ethyl 2-aroyl-3-(2-bromophenyl)propenoates. The synthesized compounds possess higher analgesic activity than the reference drug (analgin) and exhibit low toxicity.     

Synthesis and neurotropic activity of 6-thio-substituted pyrano[3,4-c]pyridine and 1-aminopyrano[4,3-d]-thieno[2,3-b]pyridine derivatives and 9-substituted pyrido[2,3-b]thieno[3,2-d]pyrimidines

Methods for the synthesis of condensed thieno[3,2-d]pyrimidines based on 3,3-dimethyl-8-morpholino-6thioxo-3,4,6,7-tetrahydro-1H-pyrano[3,4-c]pyridine-5-yl cyanide have been developed. The neurotropic properties of the synthesized compounds have been investigated. Compounds possessing anticonvulsant activity and sedative properties are found. These compounds also exhibit an activating effect that makes them analogous to the well-known drug diazepam.     

Hemolytic activity of 4-(1H-benzimidazol-1-ylmethyl)-and 4-(2-methyl-1H-benzimidazol-1-ylmethyl)phenols and their glycosides

4-(1H-Benzimidazol-1-ylmethyl)-and 4-(2-methyl-1H-benzimidazol-1-ylmethyl)phenyl-β-D-glucopyranosides have been synthesized by glycosylation of the corresponding phenols. The hemolytic activity of the synthesized compounds was studied on whole venous human donor blood at concentrations of 100, 200, and 300 μg/mL. It was established that the glycosides exhibit high biological activity and enter erythrocytes faster than do the initial phenols, which suggests that they are promising for the development of new drugs. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 41, No. 12, pp. 16–17, December, 2007.     

Synthesis and antioxidant activity of 1-(4-fluorophenyl)-1-alkyl-2-phenyl-3-morpholinopropan-1-ol hydrochlorides

Reactions of 4-fluorophenyl-β-morpholinopropiophenones with various Grignard reagents in anhydrous ether produced new tertiary aminoalcohols, 1-(4-fluorophenyl)-1-alkyl-2-phenyl-3-morpholinopropan-1-ols, that can be regarded as trihexyphenidyl (cyclodol) analogs. The antioxidant properties of the synthesized compounds were studied using a photochemiluminescence analytical method. It is established that the synthesized compounds exhibit antioxidant activity, the intensity of which depends on the length of the alkyl chain in the para-position of the benzene ring.     

Novel facile synthesis of imidazo[1,2-<Emphasis Type="Italic">b</Emphasis>]-[1,2,4,5]tetrazines with potential antimicrobial activity

Starting from 1-amino-2-methylthio-4-phenylimidazole 2, a series of the title compounds have been synthesized via its reactions with various hydrazonoyl halides 3. The mechanism of the reactions studied is discussed. The structure of the compounds prepared were elucidated on the basis of their elemental analyses, spectral data and alternate synthesis. The antimicrobial activities of the compounds prepared were screened and the results showed that most of such compounds exhibit considerable activities.     

Synthesis and Anti‐neuroinflammatory Activity of Lactone Benzoyl Hydrazine and 2‐nitro‐1‐phenyl‐1H‐Indole Derivatives as p38α MAPK Inhibitors

Inhibition of p38 mitogen‐activated protein kinases (MAPKs) would allow significant modulation of the neuroinflammation condition associated with Alzheimer's disease (AD). Inspired from the pharmacophore of natural NF‐κB and p38α MAPK inhibitor 5,6‐dehydrokawain and p38α MAPK inhibitors 1a, 1‐pyrazolyl‐3‐(4‐((2‐anilinopyrimidin‐4‐yl)oxy)napththalen‐1‐yl)ureas, and 1b , a class of indole–pyrimidinyl compounds which were patented respectively, we designed, de novo synthesized, and evaluated two kinds of novel series of lactone benzoyl hydrazine derivatives and 2‐nitro‐1‐phenyl‐1H‐indole derivatives in an effort to develop pharmacologically tractable agents to alleviate the progression of AD. Fourteen of the seventeen synthesized compounds exhibit significant inhibitory effect on the nitric oxide (NO) production induced by lipopolysaccharide (LPS)‐induced microglia activation with IC₅₀ less than the control 5,6‐dehydrokawain. Notably, compound 27 , 6‐methoxy‐2‐nitro‐1‐(1H‐1, 2, 3‐triazol‐1‐yl)‐1H‐indole, with IC₅₀ values of 1.6  μ m can markedly inhibit p38 α MAPK and NO release in BV‐2 microglial cells. The molecular dynamic (MD) simulations demonstrate that compound 27 inhibits p38 α MAPK through binding to the Glu71 and Asp168 residues. Moreover, in vitro study shows that all compounds can easily cross the blood–brain barrier (BBB) and did not exhibit any acute cellular toxicity checked by MTT assay. These investigations provide promising chemical lead candidate as anti‐neuroinflammatory agents for AD.     

Synthesis and pharmacological activity of 2-methoxyphenyl-and 2-oxyphenyl-substituted 1-dialkylaminoalkylimidazo[1,2-a]-benzimidazoles

A series of 2-methoxy-and 2-oxyphenyl-1-dialkylaminoalkylimidazo[1,2-a]benzimidazoles have been synthesized and characterized with respect to pharmacological properties. Some of the synthesized compounds exhibit antioxidant, membranotropic, antiaggregant, hemorheological, anticalmodulin, and hypotensive properties, and behave as antagonists of serotonin (5-HT_2,3) and purine (P2Y₁) receptors. The obtained data show good prospects for the synthesis and screening of biologically active substances in this class of compounds. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 40, No. 1, pp. 17–23, January, 2006.     

Chalcone Derivatives Inhibit Glutathione S‐Transferase P1‐1 Activity: Insights into the Interaction Mode of α, β‐Unsaturated Carbonyl Compounds

Resistance to chemotherapeutic drugs has long been a considerable barrier to successful treatment of many cancers and over‐expression of glutathione S‐transferase P1‐1 is correlated to carcinogenesis and resistance of cancer cells against chemotherapeutic agents. This study throws light on the role of chalcone derivatives, a new class of glutathione S‐transferase P1‐1 inhibitors potentially to overcome glutathione S‐transferase P1‐1‐mediated chemotherapy resistance. Nineteen α‐substituted chalcone derivatives were synthesized and their in vitro inhibitory effects on glutathione S‐transferase P1‐1 were determined. We interestingly found that most of these compounds showed inhibitory effect on glutathione S‐transferase P1‐1 activity. In addition, molecular field‐based similarity analysis provides the necessary three‐dimensional molecular field properties of α, β‐unsaturated carbonyl derivatives to inhibit glutathione S‐transferase P1‐1 activity. Thus, these compounds have great potential to be developed into novel chemotherapeutic sensitizers.     

Synthesis and biological properties of 5,5-diethyl-2-substituted 4-oxo-3,4,5,6-tetrahydrobenzo[<Emphasis Type="Italic">h</Emphasis>]quinazoline derivatives

A series of new derivatives of benzo[h]quinazolines containing diethyl substituents at position 5 were synthesized. The alkylation of some 2-substituted 5,5-diethyl-4-oxo-3,4,5,6-tetrahydrobenzo[h]quinazolines with methyl iodide led to N-substituted products, while a similar reaction with ethyl iodide led to a mixture of N-substituted and O-substituted products. Some of the synthesized 5,5-diethyl-4-oxo-3,4,5,6-tetrahydrobenzo[h]quinazolines exhibit pronounced antiaminooxidase and weak antitumor properties. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 41, No. 4, pp. 16–18, April, 2007.     

Partial [αMe]Aun scan of [l‐Leu11‐OMe]‐trichogin GA IV,a membrane active synthetic precursor of the natural lipopeptaibol

Abstract: We synthesized using solution‐phase methods three analogs of [l ‐Leu¹¹‐OMe] trichogin GA IV, a membrane active synthetic precursor of the lipopeptaibol antibiotic in which the N‐terminal n‐octanoyl group and each of the three Aib residues in positions 1, 4 and 8 are replaced by an acetyl group and the lipophilic C^α,α‐disubstituted glycine l ‐(αMe)Aun, respectively [partial (αMe)Aun scan]. FT‐IR absorption and CD analyses unequivocally show that the main three‐dimensional structural features of [l ‐Leu¹¹‐OMe] trichogin GA IV are preserved in the analogs. Also, [l ‐Leu¹¹‐OMe] trichogin GA IV and the three N^α‐acetylated l ‐(αMe)Aun analogs exhibit strictly comparable membrane‐modifying properties. Taken together, these results strongly favor the conclusion that a shift of the long hydrocarbon moiety from the N^α‐blocking group to the side‐chain of the 1, 4 or 8 residue does not have any significant effect on the conformational properties or the membrane activity of [l ‐Leu¹¹‐OMe] trichogin GA IV and, by extension, of the natural lipopeptaibol.     

Molluskizid wirksame Spiro-α-methylen-γ-butyrolactone

α-Methylene-γ-butyrolactones with Molluscicidal Activity The α-methylene-γ-butyrolactones 1-28 were tested in vitro for molluscicidal activity against Biomphalaria glabrata. The racemic compound 25 shows the best activity. The synthesis was carried out by modified Reformatzky reaction of the corresponding carbonyl compounds and bromomethylacrylic acid ethyl ester. 7-10, 17 and 22-27 have been synthesized for the first time.     

Synthesis and biological activity of substituted 6-alkyl(6<Emphasis Type="Italic">H</Emphasis>)-3-phenyl-1,2,4-triazolo[3,4-<Emphasis Type="Italic">b</Emphasis>]-1,3,4-thiadiazines

A series of substituted 6-alkyl(6H)-3-phenyl-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines have been synthesized by reaction of 3-alkyl-4-amino-5-thio-1,2,4-triazoles with substituted phenacylbromides in the presence of an equimolar amount of KOH. Mass spectra for the dissociative ionization by electron impact, antibacterial activity, and antitumor properties of the synthesized compounds have been studied. It was established that some compounds at doses of 50 – 100 mg/kg decrease the growth of sarcomas 45 and 37 by 35 – 47%.     

Synthesis and antimicrobial properties of 2-chloro(bromo, thiocyanato)-1-aryl-2-methyl-3-chloropropanes

A series of 2-chloro(bromo, thiocyanato)-1-aryl-2-methyl-3-chloropropanes have been synthesized. Their antimicrobial properties have been evaluated. The most effective compounds were 2-chloro-1-phenyl-2-methyl-3-chloropropane and 2-bromo-1-p-methylphenyl-(1-p-methoxyphenyl)-2-methyl-3-chloropropane. Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 42, No. 9, pp. 25–27, September, 2008.     

Synthesis and properties of equine β-melanotropin analogs with substitution in residue position 1

Five analogs of equine β-melanotropin have been synthesized by the solid phase method. The NH₂-terminal aspartic acid was substituted with amino acids (Gly, Trp, Ile, Lys and Nα-acetyl-Asp) differing widely in physicochemical properties. On the basis of their lipolytic potencies it was concluded that this position plays a negligible role in this activity.     

Physicochemical and biological evaluation of a cinnamamide derivative R,S‐(2E)‐1‐(3‐hydroxypiperidin‐1‐yl)‐3‐phenylprop‐2‐en‐1‐one (KM‐608) for nervous system disorders

A cinnamamide scaffold has been successfully incorporated in several compounds possessing desirable pharmacological activities in central and peripheral nervous system such as anticonvulsant, antidepressant, neuroprotective, analgesic, anti‐inflammatory, muscle relaxant, and sedative/hypnotic properties. R,S‐(2E)‐1‐(3‐hydroxypiperidin‐1‐yl)‐3‐phenylprop‐2‐en‐1‐one (KM‐608), a cinnamamide derivative, was synthesized, its chemical structure was confirmed by means of spectroscopy and crystallography, and additionally, thermal analysis showed that it exists in one crystalline form. The compound was evaluated in vivo in rodents as anticonvulsant, antiepileptogenic, analgesic, and neuroprotective agent. The beneficial properties of the compound were found in animal models of seizures evoked electrically (maximal electroshock test, 6‐Hz) and chemically (subcutaneous pentylenetetrazole seizure test) as well as in three animal models of epileptogenesis: corneal‐kindled mice, hippocampal‐kindled rats, and lamotrigine‐resistant amygdala‐kindled rats. Quantitative pharmacological parameters calculated for the tested compound were comparable to those of currently used antiepileptic drugs. In vivo pharmacological profile of KM‐608 corresponds with the activity of valproic acid.     

Synthesis and In Vitro Antibacterial Activity of 7‐(3‐Alkoxyimino‐4‐methyl‐4‐methylaminopiperidin‐1‐yl)‐fluoroquinolone Derivatives

A series of novel 7‐(3‐alkoxyimino‐4‐methyl‐4‐methylaminopiperidin‐1‐yl)fluoroquinolone derivatives were designed, synthesized, and characterized by ¹H‐NMR, MS, and HRMS. These fluoroquinolones were evaluated for their in‐vitro antibacterial activity against representative Gram‐positive and Gram‐negative strains. Generally, all of the target compounds have considerable antibacterial activity against the tested forty strains, and exhibit exceptional potency in inhibiting the growth of methicillin‐sensitive Staphylococcus aureus (MSSA) and methicillin‐resistant S. aureus (MRSA) ATCC33591 (MICs: 0.06 to 2 μg/mL). In particular, compounds 14 , 19 , 28 , and 29 are fourfold more potent than ciprofloxacin against MSSA 08‐49. Compounds 23 , 26 , and 27 are twofold more potent than ciprofloxacin against MRSA ATCC33591 and MSSA ATCC29213. In addition, compound 14 exhibits excellent activity (MIC: 0.06 μg/mL) against Acinetobactes calcoaceticus, which is two‐ to 16‐fold more potent than the reference drugs gemifloxacin, levofloxacin, and ciprofloxacin.     

Synthesis of 2,4,6-triisopropylbenzenesulfonic acid <Emphasis Type="Italic">N</Emphasis>-azolides and their regulatory effect on cell proliferation,energy expenditure,and apoptosis processes

A series of new N-azolides of 2,4,6-triisopropylbenzenesulfonic acid have been synthesized. Their biological activity with respect to the processes of cell proliferation, energy expenditure, and programmed cell death (apoptosis) has been studied. Convincing evidence is obtained for pronounced immunomodulating and cytoprotecting properties of two compounds (N-imidazolide and N-triazolide of 2,4,6-triiospropylbenzenesulfonic acid), which produce a positive influence directed at pathological states, in particular, cell proliferation, cell energy expenditure, and apoptosis.     

Synthesis and Pharmacological Activity of 2-Methoxyphenyl-Substituted 9-Dialkylaminoethylimidazo[1,2-a]benzimidazoles

A series of 2-methoxyphenyl-9-dialkylaminoethyl derivatives of imidazo[1,2-a]benzimidazole have been synthesized and their pharmacological properties have been studied. Some of the synthesized compounds exhibit antioxidant, radioprotector, antiarrythmic, spasmolytic, antiaggregant, anticalmodulin, and antisecretory properties. Some substances exhibit the properties of phosphodiesterase inhibitors, decrease calcium ion transport through membranes, increase myocardium resistance to hypoxia, and reduce the arterial pressure. The obtained data show good prospects for the synthesis and screening of biologically active substances in this chemical group. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 39, No. 9, pp. 26 – 32, September, 2005.     

β-ENDORPHIN: SYNTHESIS AND BIOLOGICAL ACTIVITY OF SHORTENED PEPTIDE CHAINS

Three analogs of β-endorphin have been synthesized by the solid-phase method: β_c-endorphin-(1–5)-(28–31), β_c-endorphin-(6–31) and β_h-endorphin-(1–5)-(16–31). The analgesic activities of these synthetic peptides relative to that of the parent molecule are reported. All three peptides at high doses exhibit either no or much weaker analgesic activity than β-endorphin. These data suggest that the entire β-endorphin molecule is necessary for full in vivo analgesic activity.