Discovery of naphthyl‐N‐acylhydrazone p38α MAPK inhibitors with in vivo anti‐inflammatory and anti‐TNF‐α activity

Protein kinases constitute attractive therapeutic targets for development of new prototypes to treat different chronic diseases. Several available drugs, like tinibs, are tyrosine kinase inhibitors; meanwhile, inhibitors of serine/threonine kinases, such as mitogen‐activated protein kinase (MAPK), are still trying to overcome some problems in one of the steps of clinical development to become drugs. So, here we reported the synthesis, the in vitro kinase inhibitory profile, docking studies, and the evaluation of anti‐inflammatory profile of new naphthyl‐N‐acylhydrazone derivatives using animal models. Although all tested compounds ( 3a–d ) have been characterized as p38α MAPK inhibitors and have showed in vivo anti‐inflammatory action, LASSBio‐1824 ( 3b ) presented the best performance as p38α MAPK inhibitor, with IC₅₀ = 4.45 μm , and also demonstrated to be the most promising anti‐inflammatory prototype, with good in vivo anti‐TNF‐α profile after oral administration.     

氟喹诺酮C-3酰腙的合成与抗菌活性

 目的 评价氟喹诺酮C-3位羧基被酰腙替代对其抗菌活性影响,为进一步扩大结构修饰提供新的途径。方法 第三代氟喹诺酮类药物氧氟沙星及环丙沙星为起始原料,经肼解成其相应的酰肼,然后分别与芳香醛进行缩合得系列C-3酰腙目标化合物。用琼脂稀释法研究了目标化合物体外对标准菌株金黄色葡萄球菌(S. aureus ATCC29213)、大肠埃希氏菌(E. coli ATCC25922)、铜绿假单孢菌(P. aeruginosa ATCC2785)的生长抑制活性。结果 合成了12个新的目标酰腙化合物,体外活性结果表明,氧氟沙星类酰腙化合物表现出较弱的体外抗菌活性(其MIC＞128 μg·mL^-1),而多数环丙沙星类酰腙化合物却表现出较强的体外抗菌活性(其MIC＞8 μg·mL^-1),尤其是香草醛环丙酰腙(5d)对S. aureus及E. coli的MIC≥0.5 μg·mL^-1,对P. aeruginosa的MIC≥1.0 μg·mL^-1,其抗菌活性与对照环丙沙星相当(MIC≥0.5 μg·mL^-1),而优于氧氟沙星(MIC≥2.0 μg·mL^-1)。结论 抗菌药氟喹诺酮C-3位羧基被其他取代基替代值得进一步研究。
     

一种用于细胞成像检测Al(Ⅲ)的高选择性开关型烟酰肼类荧光探针

目的:基于烟酰肼席夫碱配体,开发一种灵敏度高、选择性强的新型铝离子荧光探针。方法:通过2-羟基-1-萘甲醛和烟酰肼的缩合反应,合成一个酰腙衍生物2-羟基-1-萘甲醛烟酰腙(HL),并通过红外和核磁氢谱验证其结构。HL可通过荧光光谱检测样品中的铝离子及通过生物成像检测细胞中的铝离子。结果:HL结合铝离子后形成2:1的化合物,其荧光会发生显著的提高,并具有良好的选择性。基于密度泛函理论,通过计算验证其识别机制为激发态分子内质子转移（ESIPT）和分子内电荷转移(ICT)。HL在低浓度下和铝离子具有很好的线性关系,检测限为2.3 nmol/L。结论:基于具有良好的铝离子检测能力,此烟酰肼席夫碱配体可作为荧光探针应用于医学检验领域。     

An Acylhydrazone-Based Fluorescent Sensor for Sequential Recognition of Al3+ and H2PO4−

A novel acylhydrazone-based fluorescent sensor NATB was designed and synthesized for consecutive sensing of Al³⁺ and H₂PO₄⁻. NATB displayed fluorometric sensing to Al³⁺ and could sequentially detect H₂PO₄⁻ by fluorescence quenching. The limits of detection for Al³⁺ and H₂PO₄⁻ were determined to be 0.83 and 1.7 μM, respectively. The binding ratios of NATB to Al³⁺ and NATB-Al³⁺ to H₂PO₄⁻ were found to be 1:1. The sequential recognition of Al³⁺ and H₂PO₄⁻ by NATB could be repeated consecutively. In addition, the practicality of NATB was confirmed with the application of test strips. The sensing mechanisms of Al³⁺ and H₂PO₄⁻ by NATB were investigated through fluorescence and UV–Visible spectroscopy, Job plot, ESI-MS, ¹H NMR titration, and DFT calculations.     

Synthesis and antiviral evaluation of new N-acylhydrazones containing glycine residue

N-acylhydrazones containing glycine residue 3a-j and 8a-h were synthesized as HIV-1 capsid protein assembly inhibitors. The structures of the novel N-acylhydrazone derivatives were characterized using different spectroscopic methods. Antiviral activity demonstrated that compound 8c bearing 4-methylphenyl moiety was the most active with low cytotoxicity.     

手性氨基醇促进烯丙基三氯硅烷和酰腙的不对称烯丙基化反应

目的研究手性氨基醇在酰腙不对称烯丙基化反应中的促进作用。方法烯丙基三氯硅烷和酰腙在化合物Ⅰ[(1S,2S)-1-(对硝基苯基)-2-(3,4甲-叉二氧基苯甲胺基)-1,3丙-二醇]的作用下进行烯丙基化加成反应,产物的对映体过量值利用高效液相色谱检测。结果手性氨基醇配体化合物Ⅰ能够促进烯丙基三氯硅烷和酰腙的烯丙基化加成反应,在它的辅助作用下,烯丙基化加成产物的产率可达到57%,对映体过量值最高达到22%。温度可影响产率,反应在0~15℃条件下进行较为合适。结论首次将手性化合物Ⅰ应用于烯丙基三氯硅烷和酰腙的烯丙基化加成反应中,结果表明化合物Ⅰ能够促进该反应的发生。     

Vasodilator and antihypertensive effects of a novel N‐acylhydrazone derivative mediated by the inhibition of L‐type Ca2+ channels

New bioactive N‐acylhydrazone derivatives synthesized from safrole previously have been found to promote intense vasodilation and antihypertensive activity. In this study, we describe the synthesis and the cardiovascular effects of the new N‐acylhydrazone derivative (E)‐N‐methyl‐N′‐(thiophen‐3‐ylmethylene)benzo[d][1,3]dioxole‐5‐carbohydrazide (LASSBio‐1289). Thoracic aorta and left papillary muscles from Wistar–Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) were prepared for isometric tension recording. LASSBio‐1289 promoted relaxation of endothelium‐intact and denuded aortic rings with respective pIC₅₀ (?log IC₅₀) values of 5.07 ± 0.09 and 4.26 ± 0.09 (P < 0.001) for WKY rats and 5.43 ± 0.05 and 5.58 ± 0.07 (P > 0.05) for SHR. The vasodilator activity of LASSBio‐1289 was increased in the KCl‐contracted aorta. LASSBio‐1289 attenuated the contracture elicited by Ca²⁺ in depolarized aorta from both WKY rats and SHR. In endothelium‐intact aorta from WKY rats, LASSBio‐1289‐induced relaxation was unchanged after incubation with propranolol, ZM 241385, atropine, diphenhydramine, and HOE140, but was significantly reduced by L‐NAME and ODQ. LASSBio‐1289 decreased papillary muscles contractility only at concentrations above 200 μm . Acute intravenous injection of LASSBio‐1289 (3 mg/kg) produced a significant hypotensive response in SHR but not in WKY rats, suggesting its antihypertensive profile. The antihypertensive effect was also observed in SHR during 14 days of intraperitoneal and oral administration. In conclusion, our data demonstrated that LASSBio‐1289 induces both endothelium‐independent vasorelaxation involving the inhibition of Ca²⁺ influx through L‐type Ca²⁺ channels in aorta from WKY rats and SHR, and endothelium‐dependent relaxation mediated by the NO/cyclic GMP pathway in WKY rats.