Structure‐based Design,Synthesis, and Biological Evaluation of Isatin Derivatives as Potential Glycosyltransferase Inhibitors

Peptidoglycan glycosyltransferase (PGT) has been shown to be an important pharmacological target for the inhibition of bacterial cell wall biosynthesis. Structure‐based virtual screening of about 3 000 000 commercially available compounds against the crystal structure of the glycosyltransferase (GT) domain of the Staphylococcus aureus penicillin‐binding protein 2 (S. aureus PBP2) resulted in identification of an isatin derivative, 2‐(3‐(2‐carbamimidoylhydrazono)‐2‐oxoindolin‐1‐yl)‐N‐(m‐tolyl)acetamide ( 4 ) as a novel potential GT inhibitor. A series of 4 derivatives were synthesized. Several compounds showed more active antimicrobial activity than the initial hit compound 4 , in particular 2‐(3‐(2‐carbamimidoylhydrazono)‐2‐oxoindolin‐1‐yl)‐N‐(3‐nitrophenyl)acetamide ( 4l ), against Gram‐positive Bacillus subtilis and S. aureus with MIC values of 24 and 48 μg/mL, respectively. Saturation transfer difference (STD) NMR study revealed that there is a binding contact between 4l and the GT domain of S. aureus PBP2. Competitive STD‐NMR further proved that 4l and moenomycin A bind to GT domain in a competitive manner. Molecular docking study suggests a potential binding pocket of 4l in the GT domain of S. aureus PBP2. Taken together, compound 4l would provide a new scaffold for further development of potent GT inhibitors.     

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.     

Synthesis and Action on the Central Nervous System of 3-Substituted 2-Phenyl-2,3-dihydro-4H-1,3,2-benzoxazaphosphorin-4-one 2-Oxide and 2-Sulfide Derivatives

The synthesis of 3-substituted 2-phenyl-2,3-dihydro-4H-1,3,2-benzoxazaphosphorin-4-one 2-sulfide derivatives is described. The action of a series 2-oxide ( 1–6 ) and 2-sulfide ( 7–12 ) derivatives on the central nervous system has been evaluated. Compounds 1–4, 6, 7–10 exhibit neuroleptic activity. Derivatives of sulfide series act as antiserotoninergic drugs.     

Design,Synthesis, and Biological Evaluation of Pyrazole Derivatives

In this in vitro study, a series of novel pyrazole derivatives were designed, synthesized, and evaluated against five human cancer cell lines (PC3, A549, HL60, HCT116, and SW620) for their antiproliferative and p53‐MDM2 binding inhibitory activities. Although biological evaluations showed that this series of compounds possessed weak p53‐MDM2 inhibitory activities, most of them displayed moderate to potent antiproliferative activities against the tested cells lines. Compound 11c exhibited the best potency for MDM2 (FP‐IC₅₀ = 29.22 μm ) and demonstrated antiproliferative activities in response to the five tested cell lines (IC₅₀ = 4.09–16.82 μm ). Compared with the positive control Nutlin‐1, there was enhanced antiproliferative activity to p53‐mutated or p53‐deficient cell lines (SW620, HL60, and PC3).     

Novel Carboline Derivatives as Potent Antifungal Lead Compounds: Design,Synthesis, and Biological Evaluation

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Synthesis and Biological Evaluation of New Bischromone Derivatives with Antiproliferative Activity

The synthesis of new bischromone derivatives ( 4a – c and 5a – c ) as potential anticancer drugs is described. The difference in the reactivity between 4‐oxo‐4H‐chromene‐3‐carboxylic acid 2 (or its methyl ester 3 ) and 4‐oxo‐4H‐chromene‐3‐carbonyl chloride 1 with three different polyamines: 3,3′‐diamino‐N‐methyldipropylamine ( a ), 1,4‐bis(3‐aminopropyl)piperazine ( b ), 4,9‐dioxa‐1,12‐dodecanediamine ( c ) resulted in the formation of two different groups of products, compounds 4a – c and 5a – c , designed in agreement with the bisintercalators' structural requirements. The transformation of 4‐oxo‐4H‐chromene‐3‐carboxylic acid into 2H‐chromene‐2,4(3H)‐diones ( 5 ) was confirmed by the NMR and XRD experiments. Compounds 4a and 5a were evaluated in vitro in the highly aggressive melanoma cell line A375. An enhanced induction of apoptosis and cell cycle arrest clearly revealed that compound 5a was more potent than 4a . Compound 5a was also more active in diminishing the adhesive potential of melanoma cells. Current studies support the notion that small changes in the three‐dimensional structure of molecules might have a substantial impact on their biological activity.     

Design,Synthesis and Biological Evaluation of Pazopanib Derivatives as Antitumor Agents

A novel series of pazopanib derivatives were designed, synthesized, and evaluated for their inhibitory activity against a series of kinases including VEGFR‐2, EGFR, AKT1, ALK1, and ABL1. The anti‐angiogenic activities ex vivo of some compounds were also investigated. Compounds P2d and P2e demonstrated outstanding inhibitory activity against VEGFR‐2 and ABL1 and higher anti‐angiogenic activity compared with Pazopanib, the reference standard. These two compounds ( P2d and P2e ) could be used as novel lead compounds for further development of anticancer agents.     

Design,Synthesis, and Biological Evaluation of 1,5‐Diaryl‐1,2,4‐triazole Derivatives as Selective Cyclooxygenase‐2 Inhibitors

A series of 1,5‐diaryl‐1,2,4‐triazole derivatives were synthesized and evaluated as cyclooxygenase‐2 (COX‐2) inhibitors. The results of the preliminary biological assays in vivo showed that eight compounds 5b , 6b , 6c , 7c , 8b , 8d , 9c , and 9d have potent anti‐inflammatory activity (P < 0.01), while compounds 6b , 6c , and 9c exhibit marked potency. Compound 6c was then selected for further investigation. In the COX inhibition assay in vitro, compound 6c was identified as a potent and selective inhibitor of COX‐2 (COX‐2 IC₅₀ = 0.37 µM; SI = 0.018), being equipotent to celecoxib (COX‐2 IC₅₀ = 0.26 µM; SI = 0.015). In a rat carrageenan‐induced paw edema assay, 6c exhibited moderate anti‐inflammatory activity (35% inhibition of inflammation) at 2 h after administration of 15 mg/kg as an oral dose. A docking study also revealed that compound 6c binds in the active site of COX‐2 in a similar mode to that of the known selective COX‐2 inhibitor SC‐558.     

Anti-inflammatory Properties of New Adamantane Derivatives. Design,Synthesis, and Biological Evaluation

A series of adamantane-containing molecules consisting of two lipophilic centers which are linked by different bridges (oxime esters, oxime ethers, amides, and symmetric alcohols), were designed and synthesized as anti-inflammatory agents. Their anti-inflammatory activity was evaluated as their ability to inhibit phlogistic-induced mouse paw edema. Some of the tested compounds exhibited activity comparable to that of diclofenac, others had a weaker activity, while some oxime esters proved to enhance the inflammatory response. In all cases, activity was dose-dependent. The deacylated compound 10 was found to be the most active of the series, inhibiting inflammation due to Baker’s yeast, the mechanism of which involves mainly the activation of lipoxy-genase and/or complement systems, a property which is absent from most selective cyclooxygenase only inhibiting non-steroidal anti-inflammatory drugs (NSAIDs).     

Design,Synthesis and Biological Evaluation of Imidazo[1,2‐a]pyridine Derivatives as Novel DPP‐4 Inhibitors

A new series of DPP‐4 inhibitors with imidazo[1,2‐a]pyridine scaffold were designed by exploiting scaffold hopping strategy and docking study. Based on docking binding model, structural modifications of 2‐benzene ring and pyridine moieties of compound 5a led to the identification of compound 5d with 2, 4‐dichlorophenyl group at the 2‐position as a potent (IC₅₀ = 0.13 μm ), selective (DPP‐8/DPP‐4 = 215 and DPP‐9/DPP‐4 = 192) and in vivo efficacious DPP‐4 inhibitor. Further, molecular docking revealed that compound 5d could retain key binding features of DPP‐4 with the pyridine moiety of imidazo[1,2‐a]pyridine ring providing an additional π?π interaction with Phe357 of DPP‐4. Compound 5d might be a promising lead for further development of novel DPP‐4 inhibitor treating T2DM.     

Synthesis and Biological Evaluation of Coumarin Derivatives as Inhibitors of Mycobacterium bovis (BCG)

The coumarin compounds are an important class of biologically active molecules, which have attractive caught the attention of many organic and medicinal chemists, due to potential pharmaceutical implications and industrial applications. We herein report the one‐pot procedure for the efficient synthesis of coumarin derivatives using commercially available substrates via isocyanide‐based multicomponent condensation reactions. These compounds were evaluated for anti‐mycobacterium activity against Mycobacterium bovis (Bacillus Calmette–Guerin). The preliminary results indicated that all of the tested compounds showed relatively good activity against the test organism. The compounds 7e , 7l , and 7m showed high anti‐tuberculosis activity.     

Synthesis and Biological Evaluation of Some Pyrazoline Derivatives Bearing a Dithiocarbamate Moiety as New Cholinesterase Inhibitors

In the present study, new pyrazoline derivatives were synthesized via the reaction of 1‐(chloroacetyl)‐3‐(2‐furyl)‐5‐aryl‐2‐pyrazolines with sodium salts of N,N‐disubstituted dithiocarbamic acids. Each derivative was evaluated for its ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) using a modification of Ellman's spectrophotometric method. The compounds were also investigated for their cytotoxic properties using the MTT assay. The most potent AChE inhibitor was found as compound 7 followed by compounds 27 and 17 , when compared with eserine. Compounds effective on AChE carry the 2‐dimethylaminoethyl moiety, which resembles the trimethylammonium group and the ethylene bridge of acetylcholine. Among all compounds, compound 7 bearing 2‐dimethylaminoethyl and 3,4‐methylenedioxyphenyl moieties was also found to be the most effective inhibitor of BuChE. The MTT assay indicated that the effective concentration of compound 7 was lower than its cytotoxic concentration.     

Synthesis and Evaluation of Substituted Chroman-4-one and Chromone Derivatives as Sirtuin 2-Selective Inhibitors

A series of substituted chromone/chroman-4-one derivatives has been synthesized and evaluated as novel inhibitors of SIRT2, an enzyme involved in aging-related diseases, e.g., neurodegenerative disorders. The analogues were efficiently synthesized in a one-step procedure including a base-mediated aldol condensation using microwave irradiation. The most potent compounds, with inhibitory concentrations in the low micromolar range, were substituted in the 2-, 6-, and 8-positions. Larger, electron-withdrawing substituents in the 6- and 8-positions were favorable. The most potent inhibitor of SIRT2 was 6,8-dibromo-2-pentylchroman-4-one with an IC(50) of 1.5 μM. The synthesized compounds show high selectivity toward SIRT2 over SIRT1 and SIRT3 and represent an important starting point for the development of novel SIRT2 inhibitors.     

2-取代-9-苄基嘌呤-6-酮衍生物的合成、磷酸二酯酶-2抑制活性以及分子对接研究(英文)

目的设计和合成了6个2-取代-9-苄基-嘌呤-6-酮衍生物并测试了其对磷酸二酯酶-2的抑制活性,进而研究PDE2酶对该类抑制剂的作用方式。方法以2-氨基-2-氰基乙酰胺为原料先合成5-氨基-4-羰酰胺咪唑类衍生物,接着用微波辅助的方法合成了目标化合物。结果与结论微波辅助的方法大大缩短反应时间,从传统的加热回流20 h缩短到目前的30 min。抑制活性结果表明,化合物2b[9-苄基-2-(3,4-二甲氧基苄基)-1,9-二氢嘌呤-6-酮]有非常明显的抑制活性(IC50=1.35μmol.L-1)。配体和蛋白质对接的结果分析表明,嘌呤-6-酮衍生物同磷酸二酯酶-2的催化区域的结合主要通过氢键和π-π堆积作用实现的。     

(E)-4-芳酰氧基苯基丁烯-3-酮-2衍生物的合成及生物活性

设计合成了 11个 (E) 3 甲氧基 4 芳酰氧基苯基丁烯 3 酮 2衍生物 .其中 10个目标物未见文献报道 .体内药理筛选结果表明 ,部分目标化合物具有不同程度的抗炎活性和抗血小板聚集活性 .     

Synthesis and Anti-inflammatory Evaluation of New Sulfamoylheterocarboxylic Derivatives

A series of new sulfamoylthiophene and sulfamoylpyrazole carboxylic acid derivatives was synthesized. Some of these compounds show interesting analgesic properties and significant nonsteroidal anti-inflammatory activities in several models of inflammation.     

Synthesis,Structural Characterization and Biological Evaluation of Novel Stilbene Derivatives as Potential Antimalarial Agents

A series of benzamide‐containing stilbene derivatives was synthesized through the incorporation of short basic side‐chains in the B‐ring hydroxy position of resveratrol. Their antiplasmodial activity was evaluated in vitro against the chloroquine resistant Plasmodium falciparum D10 strain, showing IC₅₀ values between 1.5 and 80 μm , while their cytotoxicity was assessed using an human myeloid leukemia (U‐937) cell line. With a selectivity ratio of >51.02, the most selective of these derivatives, 29, also had the most lowest cytotoxic activity of the series.