Design,Synthesis, and Biological Evaluation of Andrographolide Derivatives as Potent Hepatoprotective Agents

Poor water solubility limits the clinical use of andrographolide and its derivatives. In an attempt to develop potent hepatoprotective drugs, a strategy was proposed to improve the aqueous solubility of andrographolide. Ten andrographolide derivatives were designed, synthesized, evaluated for aqueous solubility and in vivo hepatoprotective activity against CCl₄‐induced liver injury in mice. As expected, the aqueous solubility of synthetic derivatives was effectively improved. All compounds demonstrated the effect of different degrees in improving the liver enzyme (ALT and AST) activity, especially the most promising compound 9d significantly improved liver enzyme activity, with high potency to be a new lead.     

Anti-hyperalgesic effects of two sphingosine derivatives in different acute and chronic models of hyperalgesia in mice

Background

The study evaluated the effects of two sphingosine derivatives N-(2-tert-butoxycarbamylhexadecyl)glutaramide (AA) and N-(1-benzyloxyhexadec-2-yl)glutaramide (OA) in different models of hypersensitivity in mice.

Synthesis and biological evaluation of phloroglucinol derivatives possessing α‐glycosidase,acetylcholinesterase, butyrylcholinesterase,carbonic anhydrase inhibitory activity

A series of novel phloroglucinol derivatives were designed, synthesized, characterized spectroscopically and tested for their inhibitory activity against selected metabolic enzymes, including α‐glycosidase, acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and human carbonic anhydrase I and II (hCA I and II). These compounds displayed nanomolar inhibition levels and showed K_i values of 1.14–3.92 nM against AChE, 0.24–1.64 nM against BChE, 6.73–51.10 nM against α‐glycosidase, 1.80–5.10 nM against hCA I, and 1.14–5.45 nM against hCA II.

     

Design,synthesis, biological evaluations,molecular docking,and in vivo studies of novel phthalimide analogs

A series of novel phthalimide analogs containing an indole or brominated indole moiety were synthesized and their antimicrobial activity was evaluated. Compound 8 showed a broad spectrum activity, revealing 53–67% of erythromycin activity on the tested bacteria and 60–70% of miconazole activity on the tested fungi. Anticancer activity was evaluated on the cell lines HepG2, MCF‐7, A549, H1299, and Caco2. The results revealed that the new phthalimide analog 8 has broad‐spectrum anticancer activity toward all the tested cancer cell lines, followed by compound 11 , which showed good activity toward all the tested cell lines except for MCF‐7. The ability of the promising analogs 5 , 8 , and 11 to bind to topoisomerase II DNA gyrase was investigated. Caspase‐3 activation and Bcl‐2 assay of the best active derivatives 8 , 11 in addition to compound 5 were evaluated. The antifibrotic activity was studied in an in vivo model and the histopathological studies revealed that treatment with the new compound 8 improved the fibrotic liver tissues to normality.

     

Antimicrobial Activity of Novel C2-Substituted 1,4-Dihydropyridine Analogues

The antimicrobial activity of 3-methyl-5-isopropyl (or ethyl) 6-methyl-4-nitrophenyl-1,4-dihydropyridine-3,5-dicarboxylate derivatives was evaluated. Prokaryotes (bacteria) appeared to be more sensitive to their antimicrobial activity than were eukaryotes (filamentous fungi). The best antibacterial activity was shown by derivative 33, which was able to inhibit the growth of Mycobacterium smegmatis (MIC₃₃ = 9 μg.ml⁻¹), Staphylococcus aureus (MIC₃₃ = 25 μg.ml⁻¹), and Escherichia coli (MIC₃₃ = 100 μg.ml⁻¹). In addition, derivative 4 demonstrated its antibacterial power on the acid-fast bacterial species M. smegmatis and on Gram-positive S. aureus. Focusing on the structure-activity relationship, it appears that the increase in the substituent bulk at the C2 position improved the antibacterial activity of the set of compounds studied. Derivatives 33 and 4, carrying 2-cyano-3-oxo-3-phenylprop-1-en-1-yl and allyliminomethyl groups, respectively, showed significantly higher inhibition activities on all tested microorganisms in comparison with the rest of the derivatives. This enhancement was also in good correlation with different log P values (lipophilicity parameter).     

N‐substituted hydroxynaphthalene imino‐oxindole derivatives as new class of PI3‐kinase inhibitor and breast cancer drug: Molecular validation and structure–activity relationship studies

N‐substituted hydroxynaphthalene imino‐oxindole derivatives ( 5a–g ) were emerged as the inhibitors of the phosphoinositide 3‐kinase (PI3K), which is a crucial regulator of apoptosis or programmed cell death. Electron donor‐/acceptor‐substituted indole‐imine ( 5a–g ) was achieved, and the structures were elucidated by FTIR, 1H NMR, 13C NMR and HRMS. Inhibition potency of PI3Ks was assessed by competitive ELISA. Subsequently, an anticancer activity against breast cancer (MCF‐7) cell lines was evaluated. In both activities, compounds 5c , 5d and 5f showed most potent activities. Percentage inhibition for anticancer activity was 78.22 ± 1.02 ( 5c ) and 78.98 ± 1.08 ( 5f ), and the IC₅₀ was 2.02 ± 0.92 μm ( 5c ) and 1.98 ± 0.18 μm ( 5f ). Compounds 5a and 5g were found inactive for both activities, and rest all showed a moderate activity. To get more insight into the binding mode and inhibitor binding affinity, 5a–g were docked into the active site of PI3Ks p110α (PDB ID: 2ENQ). Results suggested that the hydrophobic interactions in the binding pockets of PI3Ks conquered affinity of the most favourable binding ligands ( 5c and 5f : inhibitory constant (k_i) = 102.4 and 128.23 nm ). The SAR studies demonstrate the efficiency of 5a–g as the PI3Ks precise inhibitors with the impending to treat various cancers.     

Efficacy of antiepileptic tetramethylcyclopropyl analogues of valproic acid amides in a rat model of neuropathic pain

Antiepileptic drugs (AEDs) are widely utilized in the management of neuropathic pain. The AED valproic acid (VPA) holds out particular promise as it engages a variety of different anticonvulsant mechanisms simultaneously. However, the clinical use of VPA is limited by two rare but potentially life-threatening side effects: teratogenicity and hepatotoxicity. We have synthesized several tetramethylcyclopropyl analogues of VPA amides that are non-teratogenic, and are likely to be non-hepatotoxic, and that exhibit good antiepileptic efficacy. In the present study we have assessed the antiallodynic activity of these compounds in comparison to VPA and gabapentin (GBP) using the rat spinal nerve ligation (SNL) model of neuropathic pain. TMCA (2,2,3,3-tetramethylcyclopropanecarboxylic acid, 100–250 mg/kg), TMCD (2,2,3,3-tetramethylcyclopropanecarboxamide, 40–150 mg/kg), MTMCD (N-methyl-TMCD, 20–100 mg/kg), and TMCU (2,2,3,3-tetramethylcyclopropanecarbonylurea, 40–240 mg/kg) all showed dose-related reversal of tactile allodynia, with ED₅₀ values of 181, 85, 41, and 171 mg/kg i.p., respectively. All were more potent than VPA (ED₅₀ = 269 mg/kg). An antiallodynic effect was obtained for TMCD, MTMCD and TMCU at plasma concentrations as low as 23, 6 and 22 mg/L, respectively. MTMCD was found to be non-toxic, non-sedative and equipotent to gabapentin, currently the leading AED in neuropathic pain treatment. Tetramethylcyclopropyl analogues of VPA amides have potential to become a new series of drugs for neuropathic pain treatment.     

Overcoming the protein corona in chitosan-based nanoparticles

Numerous properties of chitosan have led to its extensive use in the formulation of nanomaterials for drug delivery. However, the cationic surface of chitosan-based nanoparticles adsorbs proteins upon exposure to biological fluids, forming a phenomenon known as ‘protein corona’. This causes several effects such as decreased bioavailability and limited in vivo clinical applications of chitosan nanoparticles. Understanding and overcoming the effects of protein adsorption on chitosan nanoparticles is key for drug delivery purposes. This review focuses on the strategies implemented to increase the stability of chitosan nanoparticles in the systemic circulation by averting the formation of protein corona and the limitations of PEGylation.     

2-(4-三氟甲基苯基)-4-乙基-呋喃-3-酰胺衍生物的设计、合成及其抗肿瘤活性研究

目的 设计、合成新型抗肿瘤的2-（4-三氟甲基苯基）-4-乙基-呋喃-3-酰胺衍生物.方法 以对三氟甲基苯甲醛和丙二酸二乙酯为起始原料,经缩合、环合、酰氯化及胺解等4步反应,合成系列目标化合物.结果 设计合成了15个目标化合物,并对其进行了4种肿瘤细胞A549、QGY、HeLa和SW480的活性测试.结论 显示出较好的抗肿瘤活性,化合物5b显示出最优的高效、广谱抗肿瘤活性,值得深入研究.     

新型三唑类衍生物的合成及其抗真菌活性研究

目的：研究具有萘苄结构的三唑醇类化合物的抗真菌活性。方法设计合成了9个目标化合物;其结构通过1 H NMR、MS确证,选择8种真菌为实验菌株,根据美国国家临床实验室标准委员会（NCCLS）推荐的标准化抗真菌敏感性实验方法,进行体外抑菌活性测试。结果所有化合物对所选真菌均表现出了一定的抑菌活性,化合物1c对除烟曲霉菌以外的其他7种真菌的MIC80值＜0．125μg/ml,是伏立康唑活性的16倍。结论引入萘环和烃基侧链的目标化合物都有抗真菌活性。