Synthesis, characterization, and antimicrobial activity of copper(II) complexes with N,N′-propanediyl-bis-benzenesulfonamide and N,N′-ethanediyl-bis-2-methylbenzenesulfonamide

Copper(II) complexes of new aryldisulfonamides (L ₁  = N,N′-bis[(2-methylphenyl)sulfonyl]ethylenediamine) and L ₂  = N,N′-propanediyl-bis-benzenesulfonamide with 1,10-phenanthroline have been synthesized and characterized by using elemental analyses, FT-IR, LCMS, conductivity, and magnetic susceptibility techniques. The structures of [Cu(phen)₂]L₁ (1) and [CuL₂(phen)₂] (2) compounds have been determined. Complex (1) has also been characterized by single crystal X-ray diffraction. The complex (1) crystallizes in the triclinic system, space group P1, with cell constants a = 12.9353(8) Å, b = 13.8543(9) Å, c = 14.4513(10) Å, α = 103.593(5)°, β = 113.713(5)°, γ = 106.104(5)°, and Z = 1. The antibacterial activities of synthesized compounds were studied against Gram-positive bacteria: Staphylococcus aureus, Bacillus subtilis, and B. cereus and Gram-negative bacteria: Escherichia coli, Pseudomonas aeruginosa, and Yersinia enterocolitica by microdilution (as MICs in μg/mL) and disk diffusion (as diameter zone in mm) method. The biological activity screening showed that (1) has more activity than (2) against the tested bacteria.     

Protolytic constants of nizatidine,ranitidine and N,N′-dimethyl-2-nitro-1,1-ethenediamine; spectrophotometric and theoretical investigation

The prototropic exchange equilibria of two drugs, nizatidine (I) and ranitidine (II), and also of structurally related the N,N′-dimethyl-2-nitro-1,1-ethenediamine molecule (III) were investigated. From the changes in electronic spectra in media of various acidity several protonation constants were determined. For nizatidine pK values were −0.82, 1.95, and 6.67; for ranitidine pK values were 1.95 and 8.13; and for III was 2.60. The hydroxylation equilibrium constant in strongly alkaline media was determined too. Corresponding pK_a values were 13.23 for I, 13.26 for II and 13.76 for III. Molecular orbital calculations of electronic spectra confirmed that pK 1.95 for I and II, and pK 2.60 for III, are associated with C-protonation of nitroethenediamine fragment, while all pK_a values correspond to the addition of HO⁻ anion at the same double bond.     

In Vitro Antileishmanial,Trypanocidal, and Mammalian Cell Activities of Diverse N,N′ -Dihetaryl Substituted Diamines and Related Compounds

The leishmaniasis and Chagas diseases constitute a serious public health problem worldwide with few and ineffective treatment options. The search for new antiparasitic candidates at the initial steps of drug discovery and development is still necessary. The synthesis of 22 de novo synthetized N,N′-dihetaryl-alkyldiamine derivatives and in vitro antiparasitic activity were evaluated for the first time against intracellular and extracellular forms of Leishmania (Leishmania) infantum, L. (Viannia) panamensis, L. (Leishmania) amazonensis, and Trypanosoma cruzi. Additionally, the toxicity on mammalian cells was determined. Some of these substituted N,N′-diamines (25–35 % of the tested compounds) showed interesting results against free-living forms of parasites with activities at the inhibitory concentration (IC₅₀) level of 1.96 to 28.83 μM for L. (L.) infantum promastigotes and IC₅₀ of 0.02 to 5.31 μM for T. cruzi epimastigotes. No activity at the IC₅₀ level on intracellular amastigotes of T. cruzi was observed. However, N¹,N²-dibenzylethane-1,2-diamine 5a revealed an important activity against the intracellular amastigotes of L. infantum (IC₅₀ 25.42 μM ±0.33) and L. panamensis (IC₅₀ 58.20 μM ±3.23), while their analogue N¹,N⁴-dibenzylbutane-1,4-diamine 5c resulted in activity only against L. panamensis (IC₅₀ 11.19 μM ±0.20) without toxicity on Vero and THP-1 mammalian cells. The active compounds against intracellular parasites with low toxicity in mammalian cells may be considered for future studies in experimental models.     

Anemia and porphyria caused by N,N′-methylene-bis-acrylamide (MBA) in Mice and rats

The effects of N,N-methylene-bis-acrylamide (MBA), a cross-linking agent, on blood and bone marrow after repeated oral doses, were studied in mice and rats. Body weight, three major elements of the blood — erythrocytes, leucocytes and platelets — reticulocytes and bone marrow cells, were all reduced in either or both animals, especially in mice. Phenobarbital (PB) treatment did not greatly modify the effects of MBA in mice. An increase in free erythrocyte porphyrins and a decrease in ALA-D activity were observed in both animals. Urinary porphyrins were elevated in rats after MBA-dosing. PB-treatment did not significantly affect the elevation of porphyrins. After cessation of the MBA-dosing, all these changes were inclined to be restored to normal levels. Amounts of liver total porphyrins and microsomal P-450, and red cell fragility were within normal ranges in mice.     

酰氯用Zn(BH_4)2—N,N,N′,N′—四甲基乙二胺还原

酰氯可用硼氢化锌(由 NaBH_4与 ZnCl_2反应制备)还原生成醇,但因速度慢而无制备价值,如加入等     

Effects of N,N′-methylene-bis-acrylamide (MBA) on mouse germ cells — sperm count and morphology,and testicular pathology

The sperm count and morphology, and testicular histopathology were studied in mice over a period of 75 days following a single oral administration of 50, 100, and 200 mg/kg N.N-methylene-bis-acrylamide (MBA). With a 50 and 100 mg/kg dose, the sperm abnormality reached a maximum at 30 days, whereas the sperm count reached a minimum at 35 days. The abnormality and decrease in sperm count were both dose dependent. Following the administration of 200 mg/kg MBA, the appearance of abnormal sperm showed a diphase pattern, i.e., first at 7–15 days without any reduction of the sperm count and second at 30 days after treatment. Testicular histopathological changes showed that resting spermatocytes, succeeding leptotene and zygotene spermatocytes were either absent or reduced 1–3 days after treatment with 200 mg/kg MBA. These early histopathological changes seemed to precede both the increase in abnormal sperm and the decrease in sperm count observed 30–35 days post-treatment, and also suggested that resting spermatocytes were most sensitive to MBA exposure among various spermatogenic cells.     

Synthesis and Biological Evaluation of Ω-(N,N,N-Trialkylammonium)alkyl Esters and Thioesters of Carboxylic Acid Nonsteroidal Antiinflammatory Agents

A series of novel -(N,N,N-trialkylammonium)alkyl ester and thioester derivatives [RCOM(CH₂) _n NR ₃ ⁺ X ^–, M = O or S, n = 2–6, X = I or Cl] of 11 nonsteroidal antiinflammatory carboxylic acid agents (naproxen, ketorolac, indomethacin, ibuprofen, sulindac, ketoprofen, flufenamic acid, mefenamic acid, zomepirac, etodolac, and tifurac) was prepared and evaluated for their antiinflammatory, analgesic, and gastrointestinal erosive properties. In general, each prodrug retained the antiinflammatory activity characteristic of the corresponding parent drug but exhibited moderately to greatly reduced gastrointestinal erosive properties and significantly reduced analgetic potencies. This profile is likely due to a combination of factors including the rate of hydrolysis of the esters in the stomach, gut, and plasma, changes in the locus of absorption of the prodrug or nonsteroidal antiinflammatory drug (NSAID), and altered metabolic disposition patterns resulting from these changes. The results obtained from the compounds of this series indicate that esters of this general class may offer a means to modulate both the aqueous/lipid solubility and the hydrolytic/enzymatic cleavage indices of NSAID prodrugs which potentially possess a more favorable therapeutic ratio of antiinflammatory to gastrointestinal erosive activities.     

Effects of intraperitoneal administration of hexasodium N,N,N′,N′-ethylenediaminetetramethylenephosphonate on rat bone metabolism

The influence of hexasodium N,N,N′,N′-ethylenediaminetetramethylenephosphonate (EDITEMP.Na₆) on biochemical parameters in bone has been studied to help explain recently reported histological and pathological changes in bone induced by this agent. A single, intraperitoneal (ip) injection of EDITEMP.Na₆ (350 μmol/kg on Day 0) significantly decreased the activity of serum alkaline phosphatase (Alp) in mature male Wistar rats for up to 10 days following the injection. However, in immature rats the initial EDITEMP.Na₆-induced reduction of serum Alp activity preceded a steady increase in serum Alp activity, which was significantly elevated between Days 6 and 13. This increase coincided with a significant increase in bone Alp activity (an indicator of bone formation) on Day 8. Diaphyseal acid phosphatase (Acp) activity (an indicator of bone resorption) was significantly reduced, on Days 4 and 8 but not on Day 1, following treatment with EDITEMP.Na₆. Repeated exposure of immature male Wistar rats to EDITEMP.Na₆ (70 μmol/kg/day, ip for 7 days) also led to a significant and persistent increase in serum and bone Alp activities and a reduction in diaphyseal Acp activity. The data are in accord with published histomorphological evidence of reduced bone resorption and suggest delayed mineralization of osteoid tissue laid down during the treatment with EDITEMP.Na₆. There were only transient and limited changes in bone DNA content and [³H]thymidine incorporation throughout the studies, indicating the absence of marked cytotoxicity or altered bone cell proliferation associated with EDITEMP.Na₆-induced changes in phosphatase enzyme activities.     

Effect of a novel nicotinic receptor antagonist, N,N′-dodecane-1,12-diyl-bis-3-picolinium dibromide, on nicotine self-administration and hyperactivity in rats

Rationale and objective Recent work has shown that the novel compound N,N′-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB) may selectively block nicotinic acetylcholine receptors involved in regulating dopamine release. The current experiments examined the acute effect of bPiDDB on nicotine self-administration, sucrose-maintained responding, and nicotine-induced changes in acute and sensitized locomotor activity. Methods Rats were first trained to respond for either nicotine (i.v.) or sucrose pellets using a standard two-lever operant conditioning procedure using a fixed ratio 5 schedule of reinforcement and were then pretreated with bPiDDB (0, 0.3, 1, or 3 mg kg⁻¹) 15 min prior to the session. In separate experiments, rats were assessed for nicotine-induced changes in locomotor activity following pretreatment with bPiDDB (1 or 3 mg kg⁻¹) or mecamylamine (1 mg kg⁻¹); pretreatments were assessed with both acute and repeated nicotine (0.4 mg kg⁻¹) treatment. Results Results showed that bPiDDB dose-dependently decreased nicotine self-administration, but not sucrose-maintained responding. In the locomotor experiments, bPiDDB attenuated the hyperactivity produced by acute and repeated nicotine; however, this effect was not robust compared to mecamylamine. In contrast to mecamylamine, bPiDDB did not block the initial hypoactivity produced by acute nicotine. Conclusion Since bPiDDB decreased nicotine self-administration specifically, this novel nicotinic receptor antagonist may constitute a lead for the development of a clinically useful treatment for tobacco dependence.     

Synthesis,characterization, and cytotoxicity of N-2′-hydroxyethyl-substituted azastigmastanes

The in vitro cytotoxicity of N-2′-hydroxyethyl-substituted azastigmastanes and its precursor steroidal ketones against cancer cell lines: MCF-7, HepG2, and HCT 116; has been carried out using MTT assay. The N-2′-hydroxyethyl-substituted azastigmastanes were synthesized by bespoke version of Schmidt reaction using common Lewis acids like BF₃–OEt₂, SnCl₄ and H₂SO₄ as catalysts in substantial yields. Sulphuric acid was found to be the most suitable catalyst in terms of reaction yield and time, while SnCl₄ was found to be the weakest in case of 3β-acetoxy-N-2′-hydroxyethyl-6-aza-B-homo-5α-stigmastan-7-one and 3β-chloro-N-2′-hydroxyethyl-6-aza-B-homo-5α-stigmastan-7-one and almost inactive in case of N-2′-hydroxyethyl-6-aza-B-homo-5α-stigmastan-7-one. The products were obtained in semi-solid state and characterized by spectroscopic techniques and microanalytical data. Moreover, on the basis of IC₅₀, compound 5 was found to inhibit the cancer cells most effectively in conformity with our previous findings.     

Anti-inflammatory and ulcerogenic effects of 3-(N,N-diethylamino)propylindometacin HCl

目的：考察盐酸３（Ｎ，Ｎ二乙胺）丙基吲哚美辛（ｐｒｏｄｒｕｇ）抗炎及致溃疡作用．方法：观察大鼠角叉菜胶（Ｃａｒ）性炎症反应及口服给药胃溃疡指数的变化．结果：腹腔给药显著抑制Ｃａｒ性趾水肿，３ｈ及５ｈ的抑制率分别为３６５７％和３４５６％，与等摩尔浓度的吲哚美辛（Ｉｎｄ）差异无显著性；足趾１０μｇ／ｐａｗ给药达到６４％的抑制率，再增加剂量不能增加效果；１４１８ｍｇ·ｋｇ－１的ｐｒｏｄｒｕｇ灌胃６小时后溃疡指数显著低于同摩尔数Ｉｎｄ．结论：该药为一抗炎作用强，致溃疡性低的药物．     

Amorphous Water-Soluble Cyclodextrin Derivatives: 2-Hydroxyethyl, 3-Hydroxypropyl, 2-Hydroxyisobutyl,and Carboxamidomethyl Derivatives of β-Cyclodextrin

The pharmaceutical usefulness of natural, crystalline cyclodextrins can be improved by chemical conversions into water-soluble, amorphous mixtures of their derivatives. Reaction of -cyclodextrin with 2-chloroethanol, 3-chloropropanol, isobutylene oxide, or iodoacetamide yielded the title compounds. Distributions of the substitution degree were close to symmetrical and relatively narrow. The average substitution degrees increased with the amount of alkylating reagent used in the preparation. The number of components (half-width of distribution) increased with increasing average substitution degree. Further, distributions of the substitution degree were measured in glucose derivatives after hydrolysis of 2-hydroxyethyl, 2-hydroxypropyl, and 2-hydroxyisobutyl--cyclodextrin. The results show an uneven distribution of substitutents around the cyclodextrins, suggesting that growth of oligoglycol side chains and/or clustering of substituents on one glucose residue occurs.     

2-(N,N,N-三烷基铵)磷酸氢烷基酯的结构与抗菌活性之间的关系

2—(N,N,N—三烷基铵)磷酸氢烷基酯是一种新的抗菌剂。它具有不同的烷基和连接磷酸基和氨基的亚甲基桥,其结构式为: