Antiparasitic properties of homoallylamines and related compounds

A study of some antiparasitic properties of several homoallylamines and related tetrahydroquinolines and quinolines, previously described, was carried out using in vitro activity assays against the epimastigote form of Trypanosoma cruzi and against Trichomonas vaginalis. Unspecific cytotoxicity against murine macrophages was also studied. Although the antichagasic and trichomonacidal activities are not comparable to those of the standard drugs, nifurtimox and metronidazole, some of the compounds exhibit an interesting specific antiparasitic activity.     

The Development of a Predictive Method for the Estimation of Flux Through Polydimethylsiloxane Membranes. IV. Application to a Series of Substituted Quinolines

The steady-state flux of 33 substituted quinoline derivatives was determined in polydimethylsiloxane membranes using isopropyl alcohol as the receiver solvent. These diffusants constituted a diverse group of compounds possessing a wide range of hydrophobic, steric, and electronic characteristics. Various parameters representing these physicochemical properties such as cyclohexane–water fragmental constants, molar refractivity, Hammett's constants, intramolecular hydrogen bonding ability, melting point, and mole fraction solubility were employed to develop empirical models capable of relating the rate of diffusion to these characteristics of either the substituent on the quinoline ring or the compound itself.     

Recent advances towards the discovery of ORL-1 receptor agonists and antagonists

Since their discovery a decade ago, remarkable progress has been made toward understanding the biological function and significance of the opioid receptor-like-1 (ORL-1) receptor and its endogenous peptide ligand, nociceptin. The human nociceptin receptor, herein referred to as ORL-1, but also known as OP4 (the fourth member of opioid peptide receptor family) or nociceptin/orphanin FQ peptide (NOP) receptor, was first identified as an orphan opioid receptor with close homology to the classical μ-, κ-, and δ-opioid receptors. ORL-1 does not bind endogenous ligands of the other opioid receptors with high affinity, but instead prefers the 17 amino acid peptide nociceptin. The obvious homologies of ORL-1 to opioid receptors, and its ligand nociceptin to opioid peptide ligands, led to a period of intense investigation that resulted in a number of significant reports describing the biology of the receptor and ligand. The emerging pharmacological evidence from these reports suggests that ORL-1 agonists may be clinically useful for treatment of stress, anxiety, substance abuse (opioid and alcohol), anorexia, cachexia, cough, asthma, and possibly neuropathic pain/allodynia. The peripheral effects of nociceptin suggest that agonists may have utility in the treatment of gastrointestinal motility disorders, water retention, and hypertension. ORL-1 antagonists may be useful in enhancing cognitive function and treating locomotor disorders such as Parkinsonism. In addition to research into the fundamental biology of ORL-1 and nociceptin, noteworthy advances have been made in the discovery of new peptide and non-peptide agonists and antagonists of the ORL-1 receptor leading to a better understanding of its involvement in a variety of biological processes. This review highlights the rationale for the development of ORL-1 ligands and recent progress made by different research groups towards the development of peptidic and non-peptidic ORL-1 agonists or antagonists over the last four years. To add perspective on the commercial potential of this research area, the development status of advanced new molecules is addressed together with any pharmacological characterisation of these entities.     

Selection of the most promising 2-substituted quinoline as antileishmanial candidate for clinical trials

The antileishmanial evaluation of more than one hundred 2-substituted quinolines led us to identify three compounds for further studies: compound 1 (2-n-propylquinoline), compound 2 (2-(2methoxyethenyl)quinoline) and compound 3 (2-(2-hydroxyprop-2-enyl)quinoline). The final selection of a potential drug candidate was mainly based on chemical stability and acute oral toxicity as discriminating criteria. The most stable compound in various conditions was 2-n-propylquinoline (compound 1). Only reversible toxicity signs were observed for compound 1 at 1000 mg/kg after a treatment by oral route at a single dose and no sign was detected at 100 mg/kg. Interestingly, 2-substituted quinolines were active on a Leishmania donovani line, resistant to sitamaquine, a 8-aminoquinoline, suggesting that 2-substituted quinolines and 8-aminoquinoline probably affect a different target in L. donovani.     

Antileishmanial 2-substituted quinolines: in vitro behaviour towards biological components.

Quinolines substituted on their carbon 2 have in vivo antileishmanial activity but some of them could not be detected in plasma when assayed for pharmacokinetic studies, suggesting a sequestration of the drugs by components of the blood compartment. The present study, performed on three quinolines (1, 2 and 3), showed strong affinity for two of them (2 and 3) with red blood cells (RBCs), whereas quinoline 1 did not react with them. This process was saturable, temperature dependant and positively correlated with the in vitro antileishmanial activity of the quinolines. In addition, a rapid and spontaneous reaction with thiol groups was demonstrated for unsaturated quinolines 2 and 3. The reactivity with RBCs could be part of the compounds targeting to the parasite. These results illustrate that derivatives of the quinoline series with similar antileishmanial in vivo activity have different behaviour in the blood compartment.     

Selenium-containing heterocycles: synthesis and pharmacological activities of some new 4-methylquinoline-2(1H) selenone derivatives

Several selenolo[2,3-b]quinolines and pyrimido[4',5':4,5]selenolo[2,3-b]quinolines were prepared by annulations via reaction of NaSeH with 2-chloro-3-cyano-4-methylquinoline 1 followed by reactions with aromatic aldehydes, cycloalkanones, and acetic anhydride. Spectroscopic (IR, 1H-NMR, and MS) properties of the synthesized compounds are reported. Some selected compounds 5a, 7b, 7c, 8b-d, 9a, 11b, and 11d were investigated for their anti-inflammatory and analgesic activities; in addition, the most active compounds were tested for their ulcerogenicity and acute toxicity. Moreover, some of the test compounds 7c, 9a, 11b, and 11d were screened for their antibacterial and antifungal activities.     

Synthesis of 2-(4-substitutedbenzyl-[1,4]diazepan-1-yl)-n-(1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-7-yl)acetamides as inotropic agents

In an attempt to search for more potent positive inotropic agents, a series of N-(4,5-dihydro-1-methyl-[1,2,4]triazolo[4,3-a]quinolin-7-yl)-2-(substitutedbenzyl-[1,4]diazepan-1-yl)acetamides were synthesized and evaluated for positive inotropic activity by measuring left atrium stroke volume in isolated rabbit heart preparations. Some of these derivatives exhibited favorable activity compared with the standard drug, milrinone, among which 2-(4-(4-methylbenzyl)-[1,4]-diazepan-1-yl)-N-(4,5-dihydro-1-methyl-[1,2,4]triazolo[4,3-a]quinolin-7-yl)acetamide (6m) was the most potent, increasing stroke volume by 8.38±0.16% (milrinone 2.45± 0.06%) at 3 x 10(-5) m. The chronotropic effects of those compounds having inotropic effects were also evaluated in this work.     

孟鲁司特钠对COPD急性加重期患者肺功能和诱导痰IL-8、TNF-α的影响

摘要 目的：研究孟鲁司特钠对慢性阻塞性肺疾病（COPD）急性加重期患者肺功能和诱导痰IL-8、TNF-α的影响。方法：观察40例65~70岁COPD急性加重期患者,随机分配到治疗组和对照组中,另选20例健康老年人为健康组。健康组20例仅采用常规治疗,包括抗生素治疗、氧疗、祛痰、支气管舒张剂等;治疗组20例,在常规治疗的基础上加用孟鲁司特10 mg/d,治疗时间2周,于治疗前和治疗后测定IL-8、TNF-α水平及肺功能。结果：治疗前COPD患者IL-8和TNF-α水平高于健康组,COPD患者1秒钟用力呼气容积（FEV1）和1秒钟用力呼气容积占用力肺活量的百分比（FEV1/FVC%）低于健康组;治疗后,治疗组诱导痰IL-8和TNF-α水平低于对照组,FEV1水平高于对照组。结论：孟鲁司特钠减轻COPD急性加重期患者气道炎症,改善肺功能。