Showing papers in "Archiv Der Pharmazie in 1996"

Phenylamino-pyrimidine (PAP) derivatives: a new class of potent and selective inhibitors of protein kinase C (PKC).

Abstract: Phenylamino-pyrimidines represent a novel class of inhibitors of the protein kinase C with a high degree of selectivity versus other serine/threonine and tyrosine kinases. Steady state kinetic analysis of N-(3-[1-imidazolyl]-phenyl-4-(3-pyridyl)-2-pyrimidinamine (5), which showed potent inhibitory activity, revealed competitive kinetics relative to ATP. The adjacent H-bond acceptor of the pyrimidine moiety next to an H-bond donor of the phenylamine was found to be crucial for inhibitory activity. N-(3-Nitro-phenyl)-4-(3-pyridyl)-2-pyrimidinamine (7) preferentially inhibited PKC-alpha (IC50 = 0.79 microM) and not the other subtypes tested. The inhibition constants of PKC-alpha and the antiproliferative effect on T24 human bladder carcinoma cells showed a qualitative correlation, although with some exceptions.

Synthesis and Antifungal Activities of Myristic Acid Analogs

Abstract: Myristic acid analogs that are putative inhibitors of N-myristoyl-transferase were tested in vitro for activity against yeasts (Saccharomyces cerevisiae, Candida albicans, Cryptococcus neoformans) and filamentous fungi (Aspergillus niger). Several (+/-)-2-halotetradecanoic acids including (+/-)-2-bromotetradecanoic acid (14c) exhibited potent activity against C. albicans (MIC = 39 microM), C. neoformans (MIC = 20 microM), S. cerevisiae (MIC = 10 microM), and A. niger (MIC < 42 microM) in RPMI 1640 media. Improved synthetic methods have been developed for the synthesis of 12-fluorododecanoic acid (12a) and 12-chlorododecanoic acid (12c). Three novel fatty acids, 12-chloro-4-oxadodecanoic acid (8a), 12-phenoxydodecanoic acid (12i), and 11-(4-iodophenoxy)-undecanoic acid (13d) were also synthesized and tested.

Synthesis and evaluation of azole-substituted tetrahydronaphthalenes as inhibitors of P450 arom, P450 17, and P450 TxA2.

Abstract: In search of potential drugs for the treatment of estrogen- and androgen-dependent cancer as well as the prophylaxis of metastases, tetralones, tetralins, and dihydronaphthalenes bearing a OCH3 substituent at the benzene nucleus and an imidazol-4-yl, imidazol-1-yl, or 1,2,4-triazol-1-yl substituent in 2-position were synthesized with and without C1-spacer between the rings (compounds 2 – 26). The compounds were tested in vitro for inhibition of the three target enzymes P450 arom (human placental microsomes), P450 17 (rat testicular microsomes), and P450 TxA2 (citrated human whole blood). To examine selectivity, some compounds were further tested in vitro for inhibition of P450 18 (bovine adrenal mitochondria), P450 see (bovine adrenal mitochondria) and corticoid formation (aldosterone, corticosterone; ACTH stimulated rat adrenal tissue). In vivo, selected compounds were examined in Sprague Dawley rats regarding P450 TxA2 inhibition, reduction of plasma testosterone concentration, antiuterotrophic activity (inhibition of the uterotrophic activity of androstenedione), reduction of plasma estradiol concentration (pregnant mares' serum gonadotropin-primed rats), and mammary tumor inhibiting activity (dimethylbenzanthracene-induced tumor; pre- and postmenopausal model). In the series of imidazol-4-yl compounds, which represent a novelty in the field of azole inhibitors of steroidogenic P450 enzymes, strong inhibitors of P450 arom and/or P450 17 were found: 7-OCH3-2-(imidazol-4-ylmethylene)-1-tetralone (4) and 7-OCH3-2-(imidazol-4-ylmethyl)-tetralin (12) are among the most potent inhibitors of P450 arom in vitro known so far. Compound 4 is a selective inhibitor, whereas 12 shows in addition strong inhibition of P450 17. In contrast to 12, the 6-OCH3 derivative (compound 11) is a selective inhibitor of P450 17, being 50 times more potent than ketoconazole. Some imidazol-1-yl compounds show a marked inhibition of P450 TxA2: 2-(imidazol-1-ylmethyl)-1-tetralone (13) is a selective inhibitor of P450 TxA2, whereas 7-OCH3-2-(imidazol-1-ylmethyl)-tetralin (17) as well as 2-(imidazol-1-ylmethyl)-tetralin (16) and 7-OCH3-2-imidazol-1-yl-3,4-dihydronaphthalene (25) additionally show strong inhibition of P450 arom and P450 17. Regarding the other steroidogenic P450 enzymes as well as corticosterone formation, the compounds show only little inhibitory activity. Aldosterone formation, however, is inhibited at low concentrations. Nevertheless, 4 and 12 are more selective, i.e. inhibit aldosterone synthesis less than the well known inhibitor of P450 arom fadrozole. The compounds show activity in the aforementioned in vivo tests.

Synthesis and Antimicrobial Properties of New 4-(Alkylidene/arylidene)-amino-5-(2-furanyl)-2,4-dihydro-3H-1,2,4-triazole-3-thiones and 6-Aryl-3-(2-furanyl)-7H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazines

Abstract: A series of 4-(alkylidene/arylidene)amino-5-(2-furanyl)-2,4-dihydro- 3H-1,2,4-triazole-3-thiones (2) and 6-aryl-3-(2-furanyl)-7H-1,2,4-triazolo[3,4-b][1,3,4]thiadiazines (3) were synthesized. The configuration of 2g was assigned on the basis of 1H-NMR data. Of the new derivatives tested, only 2b, 2g, and 4f were found to be active against Staphylococcus aureus and/or Staphylococcus epidermidis (MIC 125-1.95 micrograms/ml), whereas all exhibited varying degrees of antifungal activity (MIC 25-0.8 micrograms/ml).

Aziridine-2,3-dicarboxylic Acid Derivatives as Inhibitors of Papain

Abstract: Aziridine-2,3-dicarboxylates and N-acylated derivatives have been evaluated as potential irreversible inhibitors of the cysteine proteinase papain. Dependence of inhibition activity on stereo-chemistry of the aziridine moiety has been analyzed. Whereas unsubstituted (R,R)- and (S,S)- diethyl aziridine-2,3-dicarboxylates (5) and (2) show no significant difference in inactivation the derivative acylated with BOC-(S)-Phe (BOC-(S)-Phe-(S,S)-Azi) (10) shows a 6 fold higher activity than the diastereomer BOC-(S)-Phe-(R,R)-Azi (11). Analogs acylated with Z- or BOC-(S)-Ala (9, 8) have lower second-order rate constants, indicating binding of the amino acid moiety of the inhibitors to the S2 subsite of the enzyme.

Search for the pharmacophore in kappa-agonistic diazabicyclo[3.3.1]nonan-9-one-1,5-diesters and arylacetamides

Abstract: Several heterocyclic bicyclo[3.3.1]nonan-9-ones were found to have a high affinity to kappa opioid receptors, 3,7-Diazabicyclononanones with 2,4-dipyridyl side chains were the most potent agonists whereas the corresponding 3-oxa-7-azabicyclo[3.3.1]nonan-9-one and compounds with phenyl substituents in 2 and 4 position are almost inactive. The purpose of this study was to unravel the active conformation of the bicyclononanones using well-known kappa-selective agonists such as ketocyclazocine, arylacetamides, several isoquinolines, CI-977, and four stereoisomers of EMD-61753 for comparison. In order to determine the geometry of the diazabicycles in solution pH-dependent NMR measurements of the bicycles were recorded and the results were related to the geometries of the aforementioned kappa agonists obtained from semiempirical PM3 calculations. A chair-boat conformation and a protonation at the N7 nitrogen atom of the diazabicyclononanones were found to be the pharmacophoric conformation. Comparison of the spatial arrangements, electrostatic, hydrophobic, and hydrogen bonding potentials of all kappa-selective agonists led to a model of structure-activity relationships of ligands of the kappa receptor. The arrangement of the pharmacophoric elements is characterized by an almost parallel orientation of a carbonyl and a protonated NH function in conjunction with at least one aromatic ring. Ketocyclazocine is only able to adopt this parallel orientation when the nitrogen is inverted relative to the X-ray structure. Furthermore, two binding sites for the aromatic rings are discussed. The pharmacological results of all considered bicyclononanone derivatives as well as of the four enantiomers of EMD-61753 can be understood and consistently explained in this way.

Scavenging of free radicals by tenoxicam: a participating mechanism in the antirheumatic/antiinflammatory efficacy of the drug.

Abstract: The radical scavenging activity of tenoxicam against hydroxyl (HO.), superoxide (O2.-), and peroxyl (LOO.) radicals, all of them involved in the inflammatory reactions, has been tested in different cell-free systems and by different techniques. Tenoxicam is a good scavenger of both HO. radicals (IC50 = 56.7 microM), as determined by Electron Spin Resonance (ESR) spectroscopy with the spin trapping (5,5-dimethyl-1-pyrroline N-oxide, DMPO) technique, and O2.- radicals generated by the phenazine methosulfate/reduced beta-nicotinamide adenine dinucleotide (PMS/NADH) system. The high reactivity of the drug towards HO. was confirmed by the rate constant of reaction with HO. (k approximately 10(10) M-1s-1), determined by competition kinetic studies with N,N-dimethyl-4-nitrosoaniline. In addition at a microM level (1-5 microM) it dose-dependently prevents the phycoerythrin peroxidation induced by the water-soluble azoinitiator 2,2-azobis (2-amidinopropane) dihydrochloride (ABAP), indicating a quenching effect on aqueous peroxyl radicals. The HO.-entrapping capacity was confirmed in models more close to the in vivo situation: tenoxicam inhibits the HO.-induced depolymerization of hyaluronic acid already at 15 microM and the HO.-driven lipid peroxidation in phosphatidylcholine liposomes (PCL) with an IC50 of 10 microM. In this membrane model it delays at 1-10 microM level the decomposition of phosphatidylcholine hydroperoxides to short-chain alkenals (markers: total carbonyl functions as 2,4-dinitrophenylhydrazones and conjugated dienes). The high susceptibility of the drug to HO. attack is also demonstrated by its extensive degradation (HPLC studies) when irradiated with HO. radicals. The antioxidant component of tenoxicam evidenced in this study sheds some light on the hitherto undefined mechanism of the antiinflammatory action of the drug.

Chitosan-indomethacin conjugates. Effect of different substituents on the polysaccharide molecule on drug release

Abstract: The conjugation of indomethacin with chitosan partially substituted with the hydrophilic residues triethylene glycol glutarate and triethylene glycol choline ether glutarate is described. Mucoadhesive conjugates were obtained showing gelling properties both in acid and basic environment. Among the substituents, triethylene glycol choline ether glutarate better enhances the gelling properties of the macromolecules. In all cases the kinetics of drug release from the macromoleclues approached zero order.

3‐(Octadecanoylaminomethyl)indole‐2‐carboxylic Acid Derivatives and 1‐Methyl‐3‐octadecanoylindole‐2‐carboxylic Acid as Inhibitors of Cytosolic Phospholipase A2

Abstract: 3-(1-Acylaminooctadecyl)indole-2-carboxylic acids and 3-(1-acylaminooctadecyl)-1-methylindole-2-carboxylic acids were designed and synthesized as inhibitors of cytosolic phospholipase A 2 . Enzyme inhibition was assayed by evaluation of calcium ionophore A23187-induced arachidonic acid release from bovine platelets. While compounds with 1-octadecanoylaminooctadecyl groups in position 3 of the indole were inactive inhibition data for 3-[1-(3-phenylpropionylamino)octadecyl]indole-2-carboxylic acids could not be evaluated because of lysis of the platelets. However 3-(octadecanoylaminomethyl)indole-2-carboxylic acid derivatives and 1-methyl-3-octadecanoylindole-2-carboxylic acid proved to be inhibitors of cytosolic phospholipase A 2 . The most active inhibitor was the latter compound with an IC 50 of 8 μM.

Asymmetric Synthesis and Enantiospecificity of Binding of 2-(1,2,3,4-Tetrahydro-1-isoquinolyl)-ethanol Derivatives to μ and κ Receptors

Abstract: A number of 2-(1,2,3,4-tetrahydro-1-isoquinolyl)-ethanol derivatives 7a-e have been synthesized in diastereomerically and enantiomerically pure form and have been evaluated for their binding affinity at mu and kappa opioid receptors. The amido ketones 5a-c and ent-5a-c, which were accessible by employing 3b and ent-3b for Asymmetric Electrophilic Amidoalkylation reactions, served as starting compounds. Upon reduction of 5a-c and ent-5a-c the amido alcohols l-6a-c, u-6a-c, ent-l-6a-c and ent-u-6a-c were obtained. Hydrolysis of these compounds yielded the secondary amino alcohols l-7a-c, u-7a-c, ent-l-7a-c and ent-u-7a-c and upon reductive methylation of l-7b-c, u-7b-c, ent-l-7b-c and ent-u-7b-c with CH2O and NaCNBH3 the tertiary amino alcohols l-7d-e, u-7d-e, ent-l-7d-e and ent-u-7d-e were obtained. The binding affinities of the final compounds l-7a-e, u-7a-e, ent-l-7a-e and ent-u-7a-e at both the mu and the kappa receptor were strongly dependent on their stereochemistry. In each case isomers exhibited higher affinity at the mu than at the kappa receptor. For the secondary amino alcohols 7a-c the affinity at the mu receptor followed the stereochemical order l-7 > ent-l-7 > ent-u-7 > u-7 whereas for the tertiary amino alcohols the order l-7 > u-7 > ent-l-7 > ent-u-7 was found. The stereoisomers l-7d and l-7e of the tertiary amino alcohols were found to be the most active compounds the latter exhibiting a Ki value of 7.17 which is close to that of Morphine (Ki = 1.64). In an in vivo model, the Writhing Test, both compounds l-7d and l-7e displayed high analgetic activity.

3‐(ω‐Aminoalkyl)‐5,5‐dialkyl(or spirocycloalkyl‐1′,5‐)hydantoins as New 5‐HT1A and 5‐HT2A Receptor Ligands

Abstract: A series of new 3-(ω-aminoalkyl)-5,5-disubstituted hydantoins, containing 1-phenylpiperazine, 1-(o-methoxyphenyl)piperazine or 1,2,3,4-tetrahydroisoquinoline fragments, were synthesized by standard alkylation procedures and their 5-HT 2A receptor affinities were determined. It has been shown that the investigated derivatives are recognized by 5-HT 1A and 5-HT 2A receptors due to the presence of a 1-arylpiperazine fragment; however, the terminal hydantoin moiety plays an important role in stabilization of the receptor-ligand complex. It has also been found that the two 1-phenylpiperazine derivatives 32 and 36 are new, selective 5-HT 2A receptor ligands (K i = 34 and 37 nM, respectively), whereas the derivative of 1-(o-methoxyphenyl)piperazine (38) is a new, highly potent 5-HT 1A receptor ligand (K i = 0.51 nM) with a moderate affinity for 5-HT 2A receptors (K i = 213 nM).

Nucleosides and Nucleotides, Part 144 Synthesis and Antiviral Activity of 5-Substituted (2′S)-2′-Deoxy-2′-C-Methylcytidines and -uridines[1]

Abstract: Synthesis of several 5-substituted (2'S)-2'-deoxy-2'-C-methylcytidines (8) and -uridines (6, 11) has been accomplished using radical deoxygenation of the 2'-tert-alcohols via their methyl oxalyl esters as a key reaction. Anti-herpes simplex virus type-1 and -2, and anti-varicella-zoster virus activities of the newly synthesized nucleosides were evaluated. Among them, the 5-iodouracil derivative 6e showed the most potent activity against herpes simplex virus type-1, with an EC50 of 0.14 micrograms/mL without showing cytotoxicity up to 100 micrograms/mL, but had a weak activity against herpes simplex virus type-2 and no activity against varicella-zoster virus up to 50 micrograms/mL in vitro. Although the 5-fluorocytosine derivative 8b had a potent anti-herpes simplex virus type-1 activity (EC50 = 0.22 micrograms/mL), it was rather cytotoxic to the CCRF-HSB-2 human T-cell line (IC50 > or = 1.0 microgram/mL).

From chloroquine to antineoplastic drugs? the story of antibacterial quinolones.

Abstract: Chemotherapy has not only proved valuable in treating many diseases but the history of discovery of some drugs makes exciting reading. The aim of this article is to outline one such story.

Syntheses and selective inhibitory activities of terphenyl-bisamidines for serine proteases.

Abstract: Biphenyl nitriles 5a-c, terphenyl dinitriles 11a-d, and naphthalene-bis(benzonitrile) 11c were prepared by palladium-catalyzed cross coupling reactions and subsequently converted to biphenyl amidines 8a-c and bis(benzamidines) 4a-e. Among the biphenyl amidines 8 only the meta-derivative 8b inhibits factor Xa and trypsin (Ki = 10 microM). The terphenyl bisamidine 4c does not inhibit factor Xa, trypsin, thrombin, and plasmin, while 4a and 4d are almost equipotent inhibitors of these enzymes (Ki 1-6 microM), and 4b and 4e are selective for trypsin (Ki = 0.2 and 0.3 microM; but Ki > 1 microM for factor Xa, thrombin, and plasmin). X-ray analysis of crystals of 4b complexed with bovine trypsin revealed a unique binding mode: one benzamidino group binds in the S1 site to the side chain carboxylate of Arg189. The central phenyl group is twisted away from the S2/S3 sites and the second amidino group contacts the Asn143 side chain.

Binding of Clozapine Metabolites and Analogues to the Histamine H3 Receptor in Rat Brain Cortex

Abstract: Following up the finding that the non-imidazole drug clozapine shows a considerable histamine H3 receptor antagonistic activity, a series of analogues and metabolites (clozapine-N-oxide, and N-desmethylclozapine) were tested for their affinity towards the H3 receptor using the radiolabelled H3 antagonist [125I]-iodophenpropit. Qualitative structure affinity relationships are derived for the tested compounds. In the clozapine molecule four structurally different moieties may be considered. In comparison with the affinity for the H3 receptor shown by clozapine, the following main conclusions can be drawn: The 4-piperazinyl region does not allow substituents longer than a CH3 or electronegative atoms such as an O (as in clozapine-N-oxide); the lack of the CH3 group (as in N-desmethylclozapine) also reduces the affinity for H3 receptors. Substitutions at the 5-diazepine position do not drastically alter the affinity for the H3 receptor, although a basic nitrogen is favoured over CH2, O, or S. The 8 position in ring I is an important modulatory site for H3 affinity; electronegative substituents such as chloro and fluoro in this aromatic ring increase the affinity. When these substituents are, however, present at position X2 in the ring, they disable binding to the H3 receptor. The two major clozapine metabolites (clozapine-N-oxide, and N-desmethylclozapine) will not be responsible for a possible contribution of the H3 receptor antagonism to the clinical profile of clozapine.

Synthesis and antidepressant evaluation of new hetero[2,1]benzothiazepine derivatives.

Abstract: As a part of a research program directed to the discovery of novel antidepressant agents, a series of new hetero[2,1]benzothiazepine derivatives was synthesized. Some of these compounds antagonized the ptosis and motor depression induced by tetrabenazine and were also active in the Porsolt forced swimming test.

Tolperisone: evaluation of the lidocaine-like activity by molecular modeling

Abstract: Tolperisone (1), a muscle relaxant with lidocaine-like activity, was compared to lidocaine (2) by molecular modeling methods. Conformational search analysis has been employed to find the global minima of these compounds along with numerous low energy conformations from which specific conformers were extracted that show good superimposition of the structural features important for protein binding. Two additional compounds, mepi- (3) and bupivacaine (4), were included in the analysis to validate the method as these ligands show very close structural and pharmacological relationship to lidocaine (2) and are assumed to bind to an identical site. As a result we find conformers of all four ligands that have exactly the same position and orientation of the potential sites for hydrogen bonding with the rest of the molecule showing close comparison of the three-dimensional geometry. Semiempirical calculations furthermore reveal good agreement of the electrostatic potentials of these conformations indicating similar interactions with a receptor. We conclude that tolperisone (1) and lidocaine (2) despite their chemical divergence can still attach to identical protein binding sites.

Synthesis and Activity of the Glutathione Analogue γ‐(L‐γ‐Oxaglutamyl)‐L‐cysteinyl‐glycine

Abstract: An efficient synthesis of the backbone modified glutathione analogue gamma-(L-gamma-oxaglutamyl)-L-cysteinyl-glycine (7), characterized by the presence of an urethane O-CO-NH linkage replacing the gamma-glutamylic CH2CO-NH fragment is described. The new analogue has been fully characterized by 1H- and 13C-NMR, and FAB-MS. Compound 7 was tested for inhibition of gamma-glutamyl-transferase activity and was found to be a non-competitive inhibitor of hog kidney gamma-glutamyltransferase (EC 2.3.2.2).

On the concept of a bivalent pharmacophore for SKCa channel blockers : Synthesis, pharmacological testing, and radioligand binding studies on mono-, bis-, and tris-quinolinium compounds

Abstract: The dissociation equilibrium constants (Kd values) of dequalinium (2) and the monoquinolinium compounds 1a and 1b have been determined from competition equilibrium radioligand binding with [125I]apamin on rat brain synaptic plasma membranes (SPMs). Dequalinium binds to the channel with 2 orders of magnitude higher affinity than 1a or 1b, suggesting that both quinolinium groups are needed for potent and selective SKCa channel blockade. The trisquinolinium compound 3 (1,1'-[5-[4-(4- aminoquinolinium-1-yl)but-1-yl]non-4-en-1,9-diyl]-bis-(4- aminoquinolinium)) has been synthesized and tested for inhibition of the afterhyperpolarization of rat sympathetic neurones and on the binding assay. Compound 3 shows approximately one order of magnitude higher potency than 2, being the most potent non-peptidic SKCa channel blocker reported so far (Kd approximately 30 nM). The higher affinity of 3 compared with 2 may be due to direct binding of the third quinolinium group to the channel or may arise from a reduction of the unfavorable entropy of binding via an increase of the "local concentration" of quinolinium groups.

The Anti‐inflammatory Activity of N‐Substituted Indazolones in Mice

Abstract: N-Substituted indazolones were shown to be potent anti-inflammatory and analgesic agents in mice at 8 mg/kg. In addition, the agents were able to protect against death caused by endotoxins similar to those found in chronic infections. In part, the ability of these agents to suppress the inflammatory process is due to their blockage of cytokine release, e.g.TNF alpha and IL-1, as well as their inhibition of high affinity binding to receptors on target cells of inflammation. Suppressing these receptors can be linked to the inhibition by the agents of lysosomal hydrolytic enzymes, prostaglandin cyclooxygenase and 5'-lipoxygenase activities. Free radical generation involved in inflammation was also stabilized in the presence of most of these agents.

Sulfogriseofulvin Derivatives. Synthesis by [4+2]Cycloaddition, Structure, Properties, Crystal Structure Analysis, and Antifungal Activity of Spiro[1,3‐benzoxathiole‐2,1′‐cyclohex‐2′‐en]‐4′‐one 3,3‐Dioxides

Abstract: Syntheses of substituted, especially of fluoro substituted benzoxathiole 1,1-dioxides, are described. These derivatives were transformed via the Peterson olefination into substituted 2-alkylidene derivatives 27. Diels-Alder reactions of 27 with 1,1-dimethoxy- and 1-methoxy-3-trimethylsiloxy-1,3-butadiene (30, 32) gave sulfone analogues 31 of griseofulvin (named sulfogriseofulvins). From Z-27, a number of cis-isomers with the relative stereochemistry of griseofulvin (cis-31) was prepared, and from E-isomers of 27, compounds (trans-31) with relative stereochemistry of epigriseofulvin were obtained. Some related compounds (33, 38) are synthesized by slight modifications. The stereochemistry is established by spectroscopic methods and crystal structure analyses. The compounds 31 were tested against three species of dermatophytes. The biological activities were all significantly lower than that of griseofulvin.

Research on Antifungal and Antimycobacterial Agents. Synthesis and Activity of 4-Alkylthiopyridine-2-carbothioamides

Abstract: A series of 4-alkylthiopyridine-2-carbothioamides have been prepared and evaluated in vitro for antimicrobial activity Chemical structures have been demonstrated by IR and 1H NMR data and by elemental analysis The antimycobacterial activity of these compounds against Mycobacterium tuberculosis, Mycobacterium kansasii, Mycobacterium avium, and Mycobacterium fortuitum, and the antifungal activity against Candida albicans, Candida tropicalis, Candida krusei, Candida glabrata, Trichosporon beigelii, Trichophyton mentagrophytes, Aspergillus fumigatus, and Absidia corymbifera were determined by the MIC values Compounds 3 exhibit good antimycobacterial activity compared to isoniazide A moderate antifungal activity was observed against T mentagrophytes Activity is influenced by hydrophobicity of the alkyl group

Novel histamine H3-receptor antagonists with benzyl ether structure or related moieties: synthesis and structure-activity relationships.

Abstract: In search of new histamine H 3 -receptor ligands sixteen ether derivatives of 3-(1H-imidazol-4-yl)propanol with benzylic partial structure or related moieties were prepared and investigated as H 3 -receptor antagonists. The new compounds belong to a general construction pattern developed by other histamine H 3 -receptor antagonists. Structural modifications were introduced in an attempt to optimize in vitro as well as in vivo activity. Structure-activity relationships of the new histamine H 3 -receptor antagonists are discussed. All ether derivatives showed in vitro activities in the nanomolar concentration range, but only compounds with bulky lipophilic residues were also active under in vivo conditions. The most active compound within this series was 3-(1H-imidazol-4-yl)propyl 1-naphthylmethyl ether (4n) presenting an ED 50 or 3.2 ± 1.9 mg/kg regarding enhancement of endogenous histamine in brain after p.o. administration to mice. Furthermore, comparison of the H 3 -receptor activities measured on synaptosomes of rat cerebral cortex and on guinea pig ileum gave a good correlation indicating homogeneity of central and peripheral H 3 -receptor test models. The most interesting compounds were also evaluated in functional in vitro assays with regard to their activities at histamine H 1 -, H 2 -, and muscarinic M 3 -receptors. The tested compounds showed very weak activities at these receptor subtypes demonstrating their H 3 -receptor selectivity.

Structure-activity relationship studies of novel pyrazolo[1,5-c][1,3]benzoxazines: synthesis and benzodiazepine receptor affinity.

Abstract: Some 2-arylpyrazolo[1,5-c][1,3]benzoxazin-5-ones 1 and 5-oxopyrazolo[1,5-c][1,3]benzoxazin-2-carboxylates 2 were prepared and biologically evaluated for their binding at benzodiazepine receptor (BZR) in rat cortical membranes. Structure-activity relationship studies suggest that, although proton donor d and proton acceptor at are both optional pharmacophoric descriptors, at least one of them must be present for good BZR affinity. When the proton donor d is not present, the heteroatom acceptor a 1 is necessary either in the tricyclic core or in the appended substituent at the C-2 to obtain sub-micromolar BZR affinity.

Three Lupane Derivatives from Leptospermum scoparium

Abstract: The ether extract of the aerial parts of Leptospermum scoparium cultivars yielded a lactone with a 20,29,30- trinorlupane skeleton (1). Furthermore, 2α-hydroxyursolic acid (2), platanic acid (3) and 3β,30-dihydroxy-lup-20(29)-en-28-oic acid (4) were isolated.

Syntheses and biological activities of new N1-aryl substituted quinolone antibacterials.

Abstract: A series of quinolones with a systematically varied substitution at the phenyl ring at N1 has been synthesized. Three lipophilicity descriptors (log K, log P, Rm) and the pKa values have been determined as well as the microbiological activity: The MIC values for eight different strains of three Gram-positive and three Gram-negative species and the inhibitory concentrations of DNA supercoiling (IC90 and IC100) were determined. From a principal component and a QSAR analysis relationships between antibacterial activity concerning the whole-cell system and electronic properties as well as the length of the substituents at the phenyl rings could be derived. The activity in a cell-free system was governed by the lipophilicity and the width of the substituents. It is speculated that the quinolones take a defined place in the DNA gyrase-DNA complex which is characterized by polar amino acids. This is in agreement with findings from studies of mutant gyrases.

Structure-Activity Relationship Studies of CNS Agents, Part 31[1]: Analogs of MP 3022 with a Different Number of Nitrogen Atoms in the Heteroaromatic Fragment — New 5-HT1A Receptor Ligands

Abstract: Two series of new MP 3022 analogs, i.e. 1-(o-methoxyphenyl)-4-n-propylpiperazines (3, 4a, 4b, 6-9, and 12-13) and 2-(n-propyl)- 1,2,3,4-tetrahydroisoquinolines (5a, 5b, 11a, and 11b) containing a terminal heteroaromatic system with a different number of nitrogen atoms, were synthesized and their 5-HT 1A /5-HT 2A and α 1 receptor affinity was assayed. The majority of investigated piperazines may be classified as non-selective 5-HT 1A /5-HT 2A/α1 receptor ligands. Compounds 3, 4a, 4b, 7-9a with the highest affinity for 5-HT 1A receptors (K i =4-54 nM) were tested in vivo. Their functional activity was differentiated; while 3, 8, and 9a behaved like weak antagonists of postysnaptic 5-HT 1A receptors, 4b and 7 may be classified as potential partial 5-HT 1A receptor agonists. Isomer 4a has characteristic features of a potential weak postsynaptic 5-HT 1A receptor agonist.

Synthesis and Pharmacology of Combined Histamine H1‐/H2‐Receptor Antagonists Containing Diphenhydramine and Cyproheptadine Derivatives

Abstract: The classical histamine H1-receptor antagonists diphenhydramine (3a) and cyproheptadine (9) and their derivatives (3b-d, 10) were connected with a 2-guanidinothiazole containing structure (28) derived from the H2-receptor antagonist tiotidine in order to obtain combined H1-/H2-receptor antagonists. The two moieties were not directly linked together, but were separated by a polymethylene spacer and a polar group (nitroethenediamine or urea). Thus 12 compounds were obtained that proved in vitro to possess high H1- and H2-receptor antagonist activity at the isolated guinea-pig ileum (H1) and the isolated guinea-pig right atrium (H2), respectively. The incorporation of the diphenhydramine as well as the cyproheptadine component provides high affinity to H1-receptors. The tricyclic cyproheptadine and its 10,11-dihydro derivative (30-32, 34), however, cause a decrease of H2-receptor antagonist potency compared to the diphenhydramines (29a-d, 33a-d). Using nitroethenediamine as the polar group is apparently more favourable to H1- and H2-receptor affinity as the urea function. All compounds elicit a dual mode of competitive and noncompetitive antagonism. Among the novel compounds the nitroethenediamines with 4-fluoro- or 4-methyl-substituted diphenhydramine as H1-receptor antagonist moiety (29c, d) display the most potent H1- and H2-receptor antagonist effects. The presented concept is a very promising way to combine H1- and H2-receptor antagonist properties in one molecule.

New NO-donors with antithrombotic and vasodilating activities, part 15 nitrolic acids.

Abstract: Five 1-oximino-1-nitro compounds (nitrolic acids) were prepared and tested for antithrombotic and blood pressure lowering activities. 1-Nitro-ethanone 1-oxime (1, ethylnitrolic acid) 2 h after oral administration to rats inhibited thrombus formation by a laser beam in mesenteric arterioles of rats by 69% and by 46% in venules (60 mg/kg). The blood pressure of SHR rats even at this high dose only was decreased by 10% suggesting that antithrombotic and blood pressure effects can be dissociated. The in vitro decomposition of 1 at 37 degrees C nearly exclusively gave N2O and acetic acid indicating that HNO primarily had been formed.