Phenoxy- and phenylthioalkylguanidines: synthesis and in vitro pharmacology

Impromidine analogues characterized by a phenoxy- or phenylthioalkyl moiety instead of the (5-methyl- imidazol-4-yl)-methylthioethyl substituent at the guanidino group have been prepared and tested for H₂-agonistic activity on isolated guinea pig right atrium and for H₁-antagonistic properties on guinea pig ileum. In the thioether series, compounds with two-membered carbon chain (6d, f, h) proved to be up to 5 times more potent than histamine and about 7 times more potent than the corresponding homologues 6e, g, i on the atrium, inversely, the latter compounds are up to 10 times more active than 6d, f, h as H₁-antagonists.     

Isocytosine H2-receptor histamine antagonists I. Oxmetidine and related compounds

A series of 2-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-4-pyrimidones was prepared based on cimetidine 1. The model compound 4 has modest H₂-antagonist activity as shown by its ability to antagonise histamine-stimulated tachycardia in guinea pig right atrium in vitro and inhibit histamine-stimulated gastric acid secretion in the lumen-perfused stomach of the anaesthetised rat. Investigation of the effect of substituents in the pyrimidone ring showed that suitable substitution at the 5-position gave compounds with greatly increased activity, whereas substituents at other positions in the ring were not favourable for activity. Some structure—activity and structure—toxicity correlations are discussed. Compound 32 (oxmetidine, SK&F 92994) which has the most favourable combination of properties, was selected for clinical investigation.     

Diamine-based human histamine H3 receptor antagonists: (4-Aminobutyn-1-yl)benzylamines

A series of (4-aminobutyn-1-yl)benzylamines were prepared and the SAR around three key areas: (1) the amine attached to the butynyl linker (R³R⁴N–); (2) the benzylamine moiety (R¹R²N–); and (3) the point of attachment of the benzylamine group (R¹R²N– in the ortho, meta, or para positions) was examined. One compound, 4-[3-(4-piperidin-1-yl-but-1-ynyl)-benzyl]-morpholine (9s) was chosen for further profiling and found to be a selective histamine H₃ antagonist with desirable drug-like properties. Ex vivo receptor occupancy studies established that 9s does occupy H₃ binding sites in the brain of rats after oral administration. Subcutaneous doses of 9s (10 mg/kg) given during the natural sleep phase demonstrated robust wake-promoting effects.     

Heterocyclic replacement of the central phenyl core of diamine-based histamine H3 receptor antagonists

A series of small molecules consisting of a heterocyclic core flanked by two basic functionalities were synthesized and screened for in vitro affinity at the human histamine H₃ receptor (hH₃R). Nine of the twenty-eight compounds tested were found to possess a hH₃R K_i of less than 5 nM and consisted of a diverse range of central hetero-aromatic linkers (pyridine, pyrazine, oxazole, isoxazole, thiazole, furan, thiophene, and pyrrole). One member of this series, (4-isopropyl-piperazin-1-yl)-(6-piperidin-1-ylmethyl-pyridin-3-yl)-methanone (37), was found to be a high affinity, selective antagonist that crosses the blood-brain barrier and occupies H₃ receptors after oral administration in the rat.     

Synthesis and pharmacological properties of novel benzamide derivatives acting as ligands to the 5-hydroxytryptamine 4 (5-HT4) receptor

Aseries of 4-amino-5-chloro-2-methoxy-N-(1-substituted piperidin-4-ylmethyl)benzamides was synthesized as novel gastroprokinetic agents. The affinity of these compounds for the 5-hydroxytryptamine 4 (5-HT₄) receptor was evaluated. Among these compounds, 4-amino-5-chloro-2-methoxy-N-[1-[5-(1-methylindol-3-ylcarbonylamino)pentyl]piperidin-4-ylmethyl]benzamide (3f, Y-34959) showed a higher affinity for the 5-HT₄ receptor (Ki = 0.30 nmol/L) than for other receptors, and was confirmed to be a potent 5-HT₄ receptor agonist having contractile effects in the isolated guinea-pig ascending colon (EC₅₀ = 1.2 nmol/L). In dogs, compound 3f increased gastroprokinetic motility of both the gastric antrum and the ascending colon. In addition, this effect on the colon was inhibited by azasetron, a selective 5-HT₃ receptor antagonist, demonstrating that the effect of gastroprokinetic agents having 5-HT₃ receptor antagonism on the colon were reduced compared with that of selective 5-HT₄ receptor agonists.     

Synthesis and biological activity of CCK peptides with antagonist activity for CCK-A-receptor

The synthesis of a series of cholecystokinin analogues derived from the well-known antagonist Ge 410 (Suc-Tyr(SO₃)-Met-Gly-Trp-Met-Asp-β-phenethylamide) is reported. Replacements of -Trp by -Trp, Asp by Glu and Met by Nle were carried out and the resulting changes in biological activities investigated. All compounds synthesized were tested for their ability to inhibit CCK-induced contraction on isolated guinea pig ileum. SAR studies for these compounds are discussed.     

Short-term effects of subchronic low-level hydrogen sulfide exposure on oil field workers

Objectives

To investigate the short-term effects of low-level hydrogen sulfide (H₂S) exposure on oil field workers.

Materials and methods

Observational study included 34 patients who work at an oil field. All patients were males with age range of 22–60 years (mean 37 years). The data were collected by systematic questionnaire about symptoms. The inclusion criteria of patients were symptoms related to inhalation of H₂S gas in the oil field. The complaints should be frequent and relapsed after each gas exposure and disappeared when there was no gas exposure. Exclusion criteria were the symptoms which experienced with or without H₂S exposure. The presence of H₂S gas was confirmed by valid gas detector devices.

Results

The most frequent presenting symptom was nasal bleeding. It was revealed in 18 patients (52.9 %). This followed by pharyngeal bleeding, gum bleeding, and bloody saliva (mouth bleeding) which were encountered in five cases for each complaint (14.7 %). Other less frequent presenting symptoms were tongue bleeding, bloody sputum, headache, abdominal colic, pharyngeal soreness, fatigue, and sleepiness.

Conclusions

Nasal mucosa was the most vulnerable part to H₂S effect. Inhalation of H₂S produced upper respiratory tract epithelial damage that led to bleeding from nose, pharynx, gum, tongue, trachea, and bronchi. There were no complaints of asthmatic attack upon exposure to low level of H₂S. Sunlight had a significant role in reduction of ambient air H₂S level.     

Biological evaluation of polyhalo 1,3-diazaheterocycle fused isoquinolin-1(2H)-imine derivatives

A series of polyhalo 1,3-diazaheterocycle fused isoquinolin-1(2H)-imines were evaluated in vitro against human tumour cell lines including A431, K562, HL60, HepG2 and Skov-3. As a result, some of the target compounds such as 5b, 5c, 5i, 5o, 6c, 6h and 7f showed stronger cytotoxicity against K562, H562 and Skov-3 cells in comparison with cisplatin, and the others displayed moderate cytotoxicity to A431 and HepG2. Biological investigations using the representative compounds 5c, 6c and 6h were also performed in mice bearing S₁₈₀ and H₂₂ tumours. The results indicated that these three compounds inhibit S₁₈₀ and H₂₂ growth. In addition, compounds 6c and 6h have very low acute toxicities. The preliminary analysis of structure-activity relationships is also discussed.     

Synthesis, anti-hypertensive and β-adrenoreceptor antagonist activities of 3-[4-[3-(4-aryl-1-piperazinyl)-isopropanoloxy]-phenyl]-4(3H quinazolones

The synthesis of seven 2-substituted 3-[4-[3-(4-aryl-1-piperazinyl)-isopropanoloxy]-phenyl]-4(3H)quinazolones is described. Pharmacological tests showed that some of the synthesized compounds (3a–c and 3e) possessed pronounced and sustained hypotensive effects, as tested in anesthetized normotensive rabbits, adrenoreceptor antagonist properties with respect to the α- and β-receptors and central nervous system depressant effect.     

Synthesis and preliminary pharmacological evaluation of imidazo[2,1-f]purine-2,4-dione derivatives

A series of N-8-arylpiperazinylpropyl derivatives of 1,3-dimethyl-(1H,8H)-imidazo[2,1-f]purine-2,4-dione (2–10) and amide derivatives of 1,3-dimethyl-6,7-dihydroimidazo[2,1-f]purine-2,4-(1H,3H)-dione-7-carboxylic acid (11–13) were synthesized. Compounds (2–10) evaluated in vitro were potent 5-HT_1A receptor ligands. Preclinical studies indicated that 8-[3-(N4-phenyl)-piperazin-N1-yl-propyl]-1,3-dimethyl-(1H,8H)-imidazo[2,1-f]purine-2,4-dione (2) exerts anxiolytic-like activity in the four-plate test in mice; however its effect was weaker, than that produced by Diazepam. This compound and 8-[3-(N4-2′-metoxyphenyl)-piperazin-N1-yl-propyl]-1,3-dimethyl-(1H,8H)-imidazo[2,1-f]purine-2,4-dione (3) behaved like antidepressants in the forced swimming test in mice; and their activity in that model was comparable with the effect of Imipramine. The obtained results suggested that the long-chain arylpiperazines (LCAPs) linked to tricyclic derivatives of the theophylline remain a worthy of future research for obtaining new derivatives with potential anxiolytic/antidepressant activity.     

Acyclic analogs of classical H2-antagonists: synthesis and activity of dialkylamioalkyl substituted ethers and oximes

A few dialkylaminoalkyl substituted ethers and oximes structurally related to classical H₂-antagonists have been synthesized and tested for their in vitro (guinea pig isolated atrium) H₂-antagonistic activities. Some of them are inactive others display activity. Structure—activity relationships are also discussed.     

Molecular modeling study and synthesis of quinazolinone-arylpiperazine derivatives as α1-adrenoreceptor antagonists

Three series of new 2-[(4-substituted piperazin-1-yl) methyl]quinazolin-4(3H)-ones 4a-c, Ethyl 6,7-dimethoxy-4-oxo-3-[2-(4-substituted piperazin-1-yl)acetamido/propanamido]-3,4-dihydroquinazoline-2-carboxylates 9a-f and their 2-methyl analogues 13a-l were designed and synthesized as promising α₁-adrenoceptor antagonists. The final compounds were evaluated for their in vivo hypotensive activity in normotensive cats. The most potent hypotensive quinazolinone derivatives 4b, 9e, 13i, 13j were further tested on isolated thoracic aortic rings of male Wister rats. All the tested compounds displayed α₁-blocking activity with IC₅₀ ranging from 0.2 to 0.4 mM less than prazosin. Furthermore, in the present work, molecular modeling study using Accelrys Discovery Studio 2.1 software was performed by mapping the synthesized compounds to the α₁-adrenoceptor antagonist hypothesis in order to predict their mechanism of action. Compound 13j which has the best-fitting score displayed the highest in vivo and in vitro activity among the tested compounds.     

New derivatives of 5H-pyridazino (4,5-b) indole and 1,2,4-triazino (4,5-a) indole and related compounds as inhibitors of blood platelet aggregation,anti-hypertensive agents and thromboxane synthetase inhibitors

This paper reports the synthesis of a series of hydrazone 2, tetrazole 3, triazole 4, pyrrole 5, 8, pyrazole 6, 9, 12 and 1,2,4-triazino[4,5-a]indole 10 derivatives, obtained from 4-hydrazino-8-methoxy-5H-pyridazino[4,5-b]indole 1a, 4-hydrazino-8,9-dimethoxy-5H-pyridazino[4,5-b]indole 1b, 5-methoxy- and 5,6-dimethoxyindole-2-carbohydrazides 7 and 4-hydrazino-7-methoxy-1,2,4-triazino[4,5-a]indole 11. All these new products and some other related compounds, previously reported by the authors, were studied as inhibitors of platelet aggregation in whole guinea pig blood, induced by arachidonic acid (AA), adenosine-5′-diphosphate (ADP) or collagen. Some of the most active anti-aggregating compounds were also studied as anti-hypertensive agents in spontaneously hypertensive rats (SHR) and as inhibitors of thromboxane synthetase. Acute toxicities in mice were also determined for the most interesting compounds.     

Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT(1A) activity. part 3

A number of 4-aryl-5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine with 3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole or 2-methyl-3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole residues were synthesized for further investigation of SAR in a group of pyrido[1,2-c]pyrimidine derivatives with dual 5-HT_1A/SERT activity. Compounds 8a-8p were found to be potent ligands for both 5-HT_1A and SERT with K_i ranging from 28,3 to 642 nM and 42,4 nM-1,8 μM, respectively. Moreover compounds 8a, 8b, 8c, 8d, 8e and 8g were found to be selective agonists, while 8i as an antagonist of 5-HT_1A presynaptic receptors in the inducible hypothermia test in mice.     

Synthesis, characterization and pharmacological activity of 4-{[1-substituted aminomethyl-4-arylideneamino-5-sulfanyl-4,5-dihydro-1H-1,2,4-triazol-3-yl]methyl}-2H-1,4-benzothiazin-3(4H)-ones

A new series of Schiff and Mannich bases derivatives (6) of 4-[(4-amino-5-sulfanyl-4H-1,2,4-triazol-3-yl)methyl]-2H-1,4-benzothiazin-3(4H)-one (4), derived from (3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl)acetic acid (3) were synthesized. The structures of all newly synthesized compounds were elucidated by elemental analysis, IR, ¹H NMR and mass spectral data. Synthesized compounds were evaluated for their anti-inflammatory and analgesic activity. Among the tested compounds, the (3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl)acetic acid (3) possess analgesic activity comparable to that of pentazocine; activity decreased on derivatization of the carboxylic acid group. However the anti-inflammatory activity of (3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl)acetic acid (3) increased by derivatization of the carboxylic acid group and some of the compounds showed anti-inflammatory activity comparable to that of indomethacin.     

Synthesis and biological activity of 7H-benzo[4,5]indolo[2,3-b]-quinoxaline derivatives

New 7-(2-aminoethyl)-7H-benzo[4,5]indolo[2,3-b]quinoxalines (13-20) were synthesized with high yields starting from 3H-benzo[e]indole-1,2-dione. These compounds were screened for the cytotoxicity, anti-viral activity, interferon inducing ability and DNA affinity compared with the corresponding 6-(2-aminoethyl)-6H-indolo[2,3-b]quinoxaline derivatives (1-12). It was shown, that compounds 13-20 bind to DNA stronger (lg К_a = 6.23-6.87) than compounds 1-12 (lg К_a = 5.57-5.89). Anti-viral activity is significantly reduced with annulations of benzene ring in Indoloquinoxaline moiety 13-20.     

Synthesis of 4H-chromene, coumarin, 12H-chromeno[2,3-d]pyrimidine derivatives and some of their antimicrobial and cytotoxicity activities

Condensation of 3-N,N-diethylaminophenol (1) with α-cyanocinnamonitriles (2a-c) and ethyl α-cyanocinnamates (2d-f) provided compounds 3a-f and 4a-c. 12H-Chromeno[2,3-d]pyrimidine derivatives 6, 11-13 and 16 were obtained by treatment of 4H-chromene compounds (3) with different electrophiles followed by nucleophilic reagents. Structures of these compounds were established on the basis of IR, UV, ¹H NMR, ¹³C NMR and MS data. Some of the new compounds were evaluated for antimicrobial and cytotoxicity activities.     

Synthesis, anticonvulsant and CNS depressant activity of some new bioactive 1-(4-substituted-phenyl)-3-(4-oxo-2-phenyl/ethyl-4H-quinazolin-3-yl)-urea

Several new 1-(4-substituted-phenyl)-3-(4-oxo-2-phenyl/ethyl-4H-quinazolin-3-yl)-urea were synthesized and screened for anticonvulsant, CNS depressant and sedative-hypnotic activity in the mice. After i.p. injection to mice at doses of 30, 100, and 300 mg/kg body weight synthesized compounds were examined in the maximal electroshock induced seizures (MES) and subcutaneous pentylenetetrazole (scPTZ) induced seizure models in mice. Spectroscopic data and elemental analysis were consistent with the newly synthesized compounds. The neurotoxicity was assessed using the rotorod method. Compounds E1, E6, E9, E12, P3, P4 and P6 were found to be active in the MES screen whereas E1, P4, P6 and P11 were found to be active in the scPTZ screen. All except E6, E11 and P6 showed more than 50% decrease in locomotor activity at 1 h of compound administration via actophotometer screen. CNS depressant activity screened with the help of the forced swim method resulted into some potent compounds. All the compounds were found to exhibit potent CNS depressants activity as indicated by increased immobility time. It can be concluded that newly synthesized compounds possessed promising CNS activities.     

Effects of Elevated O<Subscript>3</Subscript> and/or Elevated CO<Subscript>2</Subscript> on Lipid Peroxidation and Antioxidant Systems in <Emphasis Type="Italic">Ginkgo biloba</Emphasis> Leaves

Four-year-old seedlings of Ginkgo biloba were exposed to elevated O₃, elevated CO₂ and elevated O₃ plus elevated CO₂ in open-top chambers (OTCs) to study the responses of antioxidant system in Ginkgo biloba leaves. No significant changes in reactive oxygen production and scavenging systems were detected in seedlings exposed to high CO₂. Significant increase in H₂O₂ and MDA content were induced by elevated O₃. The ascorbate content and antioxidative enzymes activity were increased significantly by exposure to high O₃ as well. But the promoted ability in scavenging did not prevent the increase in H₂O₂ content and cell membrane lipid peroxidation. The increase was mitigated by high CO₂ in the combined exposure, but the effect was hardly significant.     

Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT1A activity: Part 2

Derivatives of 4-aryl-5,6,7,8-tetrahydro-pyrido[1,2-c]pyrimidine were synthesized. These compounds contain the 3-(4-piperidyl)-1H-indole residue or its 5-methoxy or 2-methyl derivative. In vitro binding tests were performed to determine the affinity of the compounds for the 5-HT_1A receptor and serotonin transporter (SERT) proteins in the rat brain cortex. In vivo studies, particularly the inducible hypothermia test and forced swimming test, were conducted to determine agonistic/antagonistic activity with pre- and postsynaptic 5-HT_1A receptors. Molecular modeling techniques were used to determine the binding modes of the selected compounds at the 5-HT_1A receptor and SERT. The SAR analysis showed that the presence of the 3-(4-piperidyl)-1H-indole group or its 5-methoxy derivative, as well as a para substitution with –OCH₃ or –F in the aryl ring of 4-aryl-5,6,7,8-tetrahydro-pyrido[1,2-c]pyrimidine, results in an increased affinity for both the 5-HT_1A receptors and SERT. In contrast, the presence of the 2-methyl-3-(4-piperidyl)-1H-indole group resulted in a considerable decrease in binding affinity.