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1-[4-(4-fluorophenyl)-piperazine-1-yl]-3-(2-oxopyrrolidin-1-yl)-propane hydrochloride, (I), (CDRI code No. 93/478) is a new potent anti-ischemic and anti-hypertensive agent, being developed at the Central Drug Research Institute (CDRI), Lucknow, India. A sensitive high performance liquid chromatographic assay method has been developed and validated for in process quality control and for stability studies. HPLC separation was achieved on a C(18) Purospher (Merck) column using a gradient of 0.02% tetra-methyl ammonium hydroxide (pH 7.5) and acetonitrile as mobile phase. The eluents were monitored by diode array detector at 240 and 290 nm. The lower limit of detection of I was 0.62 microg/ml, while the lower limit of quantitation was set to be 1.5 microg/ml. The calibration curves were linear in the range 1.5-62 microg/ml. Reproducibility of the method was determined by inter and intra assay variation, which were

Pharmacophoric mapping based on 3D-QSAR studies is performed on sixteen cyclic ureidobenzenesulfonamides for their β 3 -adrenergic receptor agonistic activity. The best 3D-QSAR model (with r 2 =0.877) which described the properties and distributions of 5-biophoric and 2-secondary biophoric sites, showed a good correlation between the observed and predicted activity both in training and test.

A series of nineteen substituted 1,2,3,4,6,7,12,12a-octahydropyrazino[2′,1′:6,1]pyrido[3, 4-b]indoles analogues of neuroleptic drug, Centbutindole have been studied using quantitative structure–activity relationship analysis. The derived models display good fits to the experimental data ( r >or=0.75) having good predictive power ( r cv >or=0.688). The best model describes a high correlation between predicted and experimental activity data ( r =0.967). Statistical analysis of the equation populations indicates that hydrophobicity (as measured by π R , log P (o/w) and Slog P _VSA8), dipole y and structural parameters in terms of indicator variable, (In 1 ) and globularity are important variables in describing the variation in the neuroleptic activity in the series.

Peptide deformylase catalyzes the removal of N -formyl group from the N -formylmethionine of ribosome synthesized polypeptide in eubacteria. Quantitative structure–activity relationship (QSAR) studies have been carried out in a series of β-sulfonyl and β-sulfinyl hydroxamic acid derivatives for their PDF enzyme inhibitory and antibacterial activities against Escherichia coli DC2 and Moraxella catarrhalis RA21 which demonstrate that the PDF inhibitory activity in cell free and whole cell system increases with increase in molar refractivity and hydrophobicity. The comparison of the QSARs between the cell free and whole cell system indicate that the active binding sites in PDF isolated from E. coli and in M. catarrhalis RA21 are similar and the whole cell antibacterial activity is mainly due to the inhibition of PDF. Apart from this the QSARs on some matrixmetelloproteins (COL-1, COL-3, MAT and HME) and natural endopeptidase (NEP) indicate the possibilities of introducing selectivity in these hydroxamic acid derivatives for their PDF inhibitory activity.

A series of 2-(N-aryl-N-aroyl)amino-4,5-dihydrothiazole derivatives have been synthesized via cyclocondensation of N-aryl thioureas with 2-bromoethylamine hydrobromide followed by the reaction of the product thus obtained with aroyl chlorides. Title compounds were evaluated for their antithrombotic activity in vivo in mice where one of these compound 29 provided 65% protection as compared to 77% protection offered by the standard Indomethacin. Quantitative Structure-Activity Relationship (QSAR) studies were performed on these compounds using physicochemical (hydrophobic, electronic, steric) parameter as independent and antithrombic activity as dependent parameter, where antithrombotic activity correlated best (r > 0.8) with electronic parameters (F, sigma or mu) having high statistical significance > 99.9% (F(2,22)>15.0; F(2,22alpha:0.001)=11.0) suggesting that hydrophobic, steric and resonance factors are insignificant in this set of molecules for the activity.

In view of coexistence of opioid and cholecystokinin (CCK) in the brain areas concerned with pain processing, some semirigid racemic and chiral analogues of a potent CCK receptor antagonist (benzotript) have been synthesized and tested for their modulatory role on opioid antinociception, which may be mediated by CCK-B receptor. Some of these compounds, 3e, 3g, 3h, 4a, 4b and 4h, exhibited antinociceptive potentiation comparable to benzotript and proglumide. In order to identify the essential chemical structural features important for this potentiation, molecular modeling and quantitative structure activity relationship (QSAR) studies have been carried out in the S and R enantiomers of some of these semi-rigid compounds. The 3D-biophore models, common to all molecules of the training set have been derived. These models with superimposition (match value >0.25) depicted three biophoric sites one each for, pi/hydrophobic interactions, hydrogen bonding and ionic interactions among the phenyl/pyrrole ring, indole nitrogen, amidic oxygen, pyridyl nitrogen and lone pair of amidic oxygen. The total hydrophobicity and S absolute stereochemistry are found to positively contribute to potentiation of antinociception induced by morphine and the resulting quantitative pharmacophoric model with good correlation is found to well describe the observed activity.

Synthesis and SAR studies of the title compounds have resulted in the identification of structural and physicochemical parameter (Vw) contributing for antiarrhythmic activity. Among the two most promising compounds 3a & 3b, the 3a has shown antiarrhythmic activity comparable to quinidine.

The complete structure of synthetic Daijisong, the Hayatine or (±)-Curine dimethiodide, was established unequivocally by a single-crystal X-ray analysis. Daijisong crystallizes as a trihydrate in the system, triclinic space group P1. Hayatine dimethiodide appeared as a mixture of (S)-(S) and (R)-(R) enantiomers according to the space group determined from crystallographic data (P1).

The protein tyrosine phosphatase 1B (PTP1B) is an attractive target for the treatment of type 2 diabetes. A series of substituted 1,3-benzyl urea has been synthesized and evaluated for PTP1B inhibitory, antidiabetic and antidyslipidemic activities. The most active compound of the series 5b showed 79.4% PTP1B inhibition and 20.7% blood glucose lowering in the STZ model. It also lowered the serum cholesterol level by 16.3% and significantly increased the serum HDL-cholesterol by 46.8%. The high activity of compound 5b has been explained by docking studies.

Histamine (4(5)-imidazolylethylamine) is widely distributed in nature both in the plant and the animal kingdom. It was first chemically synthesized by Windaus and Vogt [1] in 1907 because of its structural similarity with the naturally occurring alkaloid pilocarpine and the amino acid histidine. This was followed by its preparation by bacterial decarboxylation of histidine [2] and its isolation from ergot [3, 4]. It was at this time that its physiological effects, particularly as a stimulant of smooth muscle contraction were first recognized [5–7]. Later histamine was isolated from various animal tissues, thus establishing that it is a natural constituent of the body [8, 9]. In mammalian brain it is found both in neurons and non-neuronal compartments like mast cells and capillary endothelial cells [10–18]. Recently, using immunohistological techniques [19–23], it has been shown that cell bodies immunoreactive to histamine and histidine decarboxylase are restricted to the ventral part of the posterior hypothalamus and mammillary nuclei regions but send projections to almost all regions of the diencephalon and telencephalon. It is because of such a wide distribution of histamine in the body that it can participate in a variety of physiological and pharmacological processes in different systems ranging from cardiovascular to gastrointestinal and neuroendocrine [24–44].

In order to identify a pair of neuroleptic enantiomers with the highest stereoselective interaction with neuroleptic/dopamine receptors, the effects of eight pairs of neuroleptic enantiomers were tested on the specific binding of 3H-spiperone to crude homogenates of calf caudate nucleus. The ratios of the Ki values were: (+)-butaclamol/(−)-butaclamol = 3000; dexclamol/(−)-analogue = 151; (+)-isobutaclamol/(−)-isobutaclamol = 146; (−)-CTC/(+)-CTC = 109; (−)-centbutindole/(+)-centbutindole = 20; S(+)-octoclothepin/R(−)-octoclothepin = 11. Thus, the neuroleptic receptor is highly stereoselective for the rigid butaclamol derivatives, but much less so for the flexible neuroleptics. The 3H-apomorphine binding site, however, had a stereoselectivity ratio of only 7 for isobutaclamol, further suggesting that the high affinity sites (i.e. nM) for 3H-neuroleptic binding and for 3H-apomorphine binding are different.

The 1,4-substituted piperidines 16–22 have been synthesized from the 1-substituted 4-piperidones 5 and 6. The antiamoebic, antileishmanial and anticancer activities of these compounds are described. Synthese und biologische Aktivitat 1,4-disubstituierter Piperidine Die 1,4-substituierten Piperidine 16–22 wurden ausgehend von den 1-substituierten 4-Piperidonen 5 und 6 synthetisiert. Die Aktivitaten dieser Verbindungen gegenuber Amoeben, Leishmanien und lymphatischer Leukamie werden beschrieben.

Comparisons of the reactions of t-Bu 3 SiX (X usually I, but in some cases OSO 2 CF 3 or Cl) and the corresponding TsiMe 2 X species (Tsi = Me 3 Si) 3 )C) have led to the following conclusions: (a) Under conditions in which TsiSiMe 2 I is thought to react via a silicocationic intermediate (mainly, solvolysis in CF 3 CO 2 H or reactions with silver salts), this iodide is much more reactive than t-Bu 3 SiI. (b) The reactivity difference between the two iodides is markedly smaller in reactions with alkali metal salts, i.e. S N 2 processes, the TsiSiMe 2 I commonly being ca. 3–8 times the more reactive. (c) In methanolysis and hydrolysis under conditions in which an S N 2-intermediate mechanism may operate, the differences in reactivity between TsiSiMe 2 X and t-Bu 3 SiX compounds (X = I or OSO 2 CF 3 ) vary considerably with the medium, with the former usually, though not always, the more reactive, but again the differences are much smaller than those in the reactions mentioned under (a) in which the ease of breaking of the Si-X bond is the greatly dominant factor. (d) The differences between the reactivities of iodides and the corresponding chlorides in these highly crowded systems are smaller in reactions in which participation by the nucleophile is important than in those in which the ease of ionization of the Si-X bond is dominant; in reaction with NaN 3 , KOCN or KSCN in MeCN, t-Bu 3 SiCl is more reactive than t-Bu 3 SiI.

1. In cats anaesthetized with chloralose, adrenoceptor and cholinoceptor agonists and antagonists were localized to the posterior hypothalamus (PH), lateral medullary pressor area (LMPA) and spinal autonomic loci to delineate the role of central cholinoceptors and adrenoceptors in cardiovascular control. 2 All along the neuroaxis, the alpha-adrenoceptors seem to subserve an inhibitory and the beta-adrenoceptors a facilitatory role in cardiovascular control. There appear to be a predominance of alpha-adrenoceptors at the medullary level and beta-adrenoceptors at the hypothalamic level. 3 The nicotinic cholinoceptors at the hypothalamic, medullary and spinal levels were facilitatory, whereas muscarinic cholinoceptors were inhibitory for cardiovascular control. However, muscarinic receptors were undetectable at the posterior hypothalamus. 4 The central cardiovascular effects of nicotine are attributed to nicotinic receptor activation and release of central catecholamines. 5 There appears to be a relationship between central cholinergic and adrenergic mechanisms in cardiovascular control.

Eight new ω-(indol-3-yl)alkane carboxamides were synthesized and studied for their antiinflammatory activities against carrageenin induced paw oedema in albino rats. Six compounds exhibited various degrees of antiinflammatory activity, two compounds showed no activity. The most potent compound of the present series, 1-(indol-3-yl)-N-{4-[1-(4-methylphenyl)piperazinyl]phenyl}acetamide (7) as well as phenylbutazone showed dose dependent inhibition of rat paw oedema. The ulcerogenic activities of compound 7 and phenylbutazone were also dose dependent. However, 7 showed a much lower ulcerogenic activity. In view of its potent antiinflammatory activity, minimal ulcerogenic liability and low acute toxicity compound 7 appears promising. Indolylverbindungen als entzundungshemmende Substanzen Acht neue Indolyl-3-alkyl-carboxamide wurden synthetisiert und auf ihre entzundungshemmende Aktivitat an der carrageenininduzierten Entzundung der Pfoten von Albino-Ratten getestet. Zwei dieser Substanzen hatten keine entzundungshemmende Aktivitat, die anderen sechs zeigten in unterschiedlichem Grad eine solche Aktivitat. Die starkste entzundungshemmende Aktivitat zeigt Indolyl-3-methyl-1-aminophenyl-4′-(p-tolyl)piperazinocarboxamid (Substanz 7). 7 besitzt wie auch Phenylbutazon eine ulcerogene Aktivitat, jedoch ist diese bedeutend schwacher als die des Phenylbutazons. Substanz 7 scheint vielversprechend wegen ihrer schwacheren ulcerogenen Aktivitat und ihrer niedrigen akuten Toxizitat.

The crystal structure of t-Bu2Si(OH)2 consists of hydrogen-bonded dimers linked by further hydrogen bonding into (distorted) ladder chains, the type of structure previously postulated for solid i-Bu2S(OH)2 to account for its ability to give a liquid crystal on heating. The six-membered rings of the dimers have a chair conformation with adjacent chairs inverted with respect to one another. The structure of the ladder chains is similar to that in t-Bu2Ge(OH)2, but the packings of the chains in the crystal are different.

The germanium chloride (Me3Si)2C(SiMe2OMe)(GeMe2Cl)(2a) has been found to be much more reactive than the related chloride (Me3Si)3C(GeMe2Cl)(1) towards silver salts. The compound (Me3Si)2C(SiMe2OMe)(GeMe3) is correspondingly much more reactive than (Me3Si)3C(GeMe3) towards CF3CO2H. These findings are consistent with anchimeric assistance by the γ-OMe group to leaving of Cl– or Me–, but a firm conclusion that such an effect operates was prevented by the finding that (2a) is also much more reactive than (1) towards NaOMe–MeOH. The methanolysis of (2a) in NaOMe–MeOH differs mechanistically from that of the analogous silicon chloride (Me3Si)2C-(SiMe2OMe)(SiMe2Cl).

An X-ray diffraction study has shown that t-Bu2Si(OH)F crystallizes as hydrogen-bonded tetramers. The fluoride ligand does not take part in the hydrogen bonding, which involves OH--O linkages with an OH--O angle of 160°; the O---O---O angles are 89.7(3)°, but the four oxygen atoms are not quite coplanar (space group I 4 ). The t-BuSiBu-t angle is 120.5(6)°.

The iodide (Me2PhSi)3CSiMe2 I was found to react with MeCN in the presence of NaN3 to give the (PhMeSi)3CSiMe2 NNC(Me)Nz.dbondN , the structure of which was determined by an X-ray diffraction study. Some of the corresponding trimethyl-silyl-substituted tetrazole was formed from Me3SiI under similar conditions.

Tin-119 CP/MAS high resolution NMR spectra have been obtained for three solid diorganotin compounds of potential biochemical significance. The data are discussed in terms of their chemical structures, particularly the coordination about tin.

Eleven quinazolones were synthesized by condensing 2-phenylanthranil with a suitable peptide in pyridine. The compounds synthesized were characterised by their sharp melting points, elemental analysis and IR spectra. The newly synthesized compounds were tested for their amoebicidal and fungicidal activities. Some of the compounds showed promising results.

The compound TsiGeMe2Cl (1)[Tsi =(Me3Si)3C] has been shown to react with AgO2CCF3 in CF3CO2H and with AgBF4 or AgO3SCF3 in CH2Cl2 to give TsiGeMe2Y (Y = O2CCF3, F, or O3SCF3). In contrast, reaction of (Me3Si)2C(GeMe3)(SiMe2Br)(2), (i) with AgO2CCF3 in CF3CO2H gives a 35 : 65 mixture of the unrearranged (Me3Si)2C(GeMe3)(SiMe2O2CCF3) and the rearranged TsiGeMe2O2CCF3, (ii) with AgO3SCF3 in CH2Cl2 gives almost exclusively the rearranged TsiGeMe2O3SCF3, and (iii) with AgBF4 in CH2Cl2 gives a 70:30 mixture of unrearranged (Me3Si)2C(GeMe3)(SiMe2F) and the rearranged TsiGeMe2F. It is suggested that the reactions of (2) involve anchimeric assistance to leaving of Br– by an Me group of the GeMe3 ligand, with formation of a cationic intermediate having an Me bridge between Ge and Si. Since compound (2) is much more reactive towards silver salts than TsiSiMe2Br it appears that an Me group attached to Ge provides markedly more assistance than one attached to Si. The absence of rearrangement in reactions of (1) indicates that cationic intermediates are not formed in this case.

The 1,4-substituted piperidines 16–22 have been synthesized from the 1-substituted 4-piperidones 5 and 6. The antiamoebic, antileishmanial and anticancer activities of these compounds are described. Synthese und biologische Aktivitat 1,4-disubstituierter Piperidine Die 1,4-substituierten Piperidine 16–22 wurden ausgehend von den 1-substituierten 4-Piperidonen 5 und 6 synthetisiert. Die Aktivitaten dieser Verbindungen gegenuber Amoeben, Leishmanien und lymphatischer Leukamie werden beschrieben.