Design,synthesis, biological evaluation and in silico studies of N-(pyridin-2-yl)-benzamides derivatives as quorum sensing inhibitors

The emergence of bacterial resistance against chemical treatment is a big threat to the efficacy of bacterial infection treatment. One of the major reasons for resistance to antimicrobial agents is growth of microorganisms in biofilm. An alternative treatment by developing novel anti-biofilm agents had led to the concept of quorum sensing (QS) inhibition, which primarily targets QS signaling system by disrupting cell-cell communication. Therefore, this study focuses to develop novel antimicrobial agents which work by QS inhibition and act as anti-biofilm agents against Bacillus Subtilis and Pseudomonas Aeruginosa. In this work, a natural product-like scaffolds from Asinex library were screened and N-pyridin-2-yl-benzamide moiety was chosen to design and synthesize. Synthesized compounds were evaluated for potential anti-biofilm activity for the aforesaid microorganisms and also checked for cell viability assay, where two potent compounds 3a and 3c showed their static biofilm activity to ∼59% and ∼58% at 100 μM, respectively against Bacillus subtilis. These synthesized compounds were investigated for physicochemical parameters and binding mode prediction through molecular modelling tools. The interactions and stability of these compounds showed better affinity towards TasA and LasR proteins from Bacillus subtilis and Pseudomonas aeruginosa, respectively. Furthermore, molecular dynamic simulation for 100 ns was executed in order to appreciate the stability of the protein and ligand complex. The overall results promised that N-pyridin-2-yl-benzamide derivatives can be discovered as a lead in developing potent anti-quorum sensing agents against various bacteria.     

Design,synthesis and biological evaluation of novel non-azole derivatives as potential antifungal agents

A series of 3-substituted quinazolinones, 2-substituted quinoxalines and 2-substituted benzopyrans were synthesized and evaluated for their antifungal activity in vitro. The new compounds revealed excellent in vitro antifungal activity with broad spectrum. The structure-activity relationships (SARs) of the derivatives were analyzed. Compound 9A2 exhibits better antifungal activity against 5 tested fungi in vitro than fluconazole, especially against Trichophyton rubrum and Microsporum gypseum. This study provides a series of novel lead compounds for the development of non-azole antifungal agents.     

2-巯基苯并咪唑衍生物的设计、合成及抗肿瘤活性研究

为了从苯并咪唑类衍生物中寻找新的活性化合物,以溴乙酸作为起始原料,设计合成了17个2-巯基苯并咪唑衍生物4a～4q。采用噻唑蓝(MTT)法测试了目标化合物对人宫颈癌细胞(He La)、人乳腺癌细胞(MCF-7)、人肝癌细胞(HepG2)、人非小细胞肺癌细胞(A549)的增殖抑制活性。结果显示,大部分化合物具有较好的抗肿瘤活性,其中,((1H-苯并[d]咪唑-2-基)硫基)-1-(4-二苯甲基哌嗪-1-基)乙烷-1-酮(4l)对HepG2细胞的抑制活性最好,IC_(50)值为12. 62±0. 78μmol/L,接近于对照药品吉非替尼(9. 72±0. 38μmol/L)。此外,利用分子对接方法对目标化合物的构效关系进行了讨论。     

Design,synthesis and biological evaluation of O-linked indoles as VEGFR-2 kinase inhibitors (I)

Inhibition of VEGFR-2 signaling pathway has already become one of the most promising approaches for the treatment of cancer. In this study, we describe the design, synthesis, and biological evaluation of a series of O-linked indoles as potent inhibitors of VEGFR-2. Among these compounds, 18 showed significant anti-angiogenesis activities via VEGFR-2 in enzymatic proliferation assays, with IC₅₀ value of 3.8 nmol/L. Kinase selectivity profiling revealed that 18 was a multitargeted inhibitor, and it also exhibited good potency against VEGFR-1, PDGFR-α and β.     

Identification,synthesis and evaluation of CSF1R inhibitors using fragment based drug design

Colony-stimulating factor 1 receptor is a type III receptor protein tyrosine kinase belonging to PDGFR family. CSF1R signaling is essential for differentiation, proliferation and survival of macrophages. Aberrant expression of CSF1R appears to be an attractive target in several cancer types. Higher expression of CSF1R ligands correlates to tumor progression. CSF1R inhibitors have been shown to suppress cancers. We have attempted an in silico fragment derived drug discovery approach by screening ˜25,000 in-house compounds as potential CSF1R inhibitors. Using FBDD approach we have identified six diverse fragments that exhibit affinity towards hinge region of CSF1R. Some of the fragments 5-nitroindole and 7-azaindole and their derivatives were synthesized for further evaluation. The in silico and in vitro enzyme activity studies reveal moderate inhibition of CSF1R kinase activity by 5-nitroindole and good inhibition by 7-azaindole fragments. Bio and chemiinformatics studies have shown that 7-azaindole compounds have better membrane permeability and enzyme inhibition properties. Molecular docking studies show that the amino acid residues 664–666 in the hinge region of the cytosolic domain of CSF1R to be the preferred region of binding for nitroindole and azaindole derivatives. Further optimization and biological analysis would identify these fragments as potential and promising leads as CSF1R inhibitors.     

Design,synthesis and biological evaluation of LpxC inhibitors with novel hydrophilic terminus

In order to develop novel LpxC inhibitors with good activities and metabolic stability, two series of compounds with hydrophilic terminus have been synthesized and their in vitro antibacterial activities against Escherichial coli and Pseudomonas aeruginosa were evaluated. Especially, compounds 22b and c exhibited comparable antibacterial activities to CHIR-090 and better metabolic stability than CHIR-090 and LPC-011 in liver microsomes (rat andmouse), which indicated the terminal methylsulfone may be a preferred structure in the design of LpxC inhibitors and worthy of further investigations.     

Design,synthesis and biological evaluation of E-ring modified evodiamine derivatives as novel antitumor agents

A series of novel E-ring modified evodiamine derivatives were designed and synthesized as antitumor agents. Their capacity to interfere with the catalytic activity of topoisomerase Ⅰ and Ⅱ was evaluated by the relaxation assay. In vitro antitumor activity results revealed that compound 12 showed good antitumor activity with a broad spectrum. Its binding modes with topoisomerase Ⅰ and Ⅱ were clarified by molecular docking.     

Design and synthesis of some novel pyridothienopyrimidine derivatives and their biological evaluation as antimicrobial and anticancer agents targeting EGFR enzyme

A new series of pyridothienopyrimidine derivatives was designed and evaluated as antimicrobial and anticancer agents. The target compounds were synthesized starting with 3-aminothieno[2,3-b]pyridine-2-carboxamide derivative 1 which underwent cyclocondensation reaction with aromatic aldehydes to give the key intermediates 2a,b. By further treatment of 2a,b with various reagents, the target 2,4-disubstituted-pyrido[3′,2′:4,5]thieno[2,3-d]pyrimidines 3a,b–11a,b were obtained. To evaluate the antimicrobial activity of the new compounds, they were tested against five bacterial and five fungal strains. Compounds 6c, 8b, 9a and 9b revealed the most significant antimicrobial activity against the tested microorganisms with MIC values range (4–16 μg/mL). Also, compounds 2a,b–11a,b were screened for their in vitro cytotoxic activity against HepG-2 and MCF-7 cancer cell lines compared with doxorubicin and cisplatin as references drugs. Moreover, compounds (2b, 4a, 6a, 7b, 7c and 9a) which exhibited the most potent anticancer activity, were further subjected to EGFR^WT enzyme inhibition assay utilizing erlotinib as a standard drug. The compounds 6a, 7b, 7c and 9a which showed the most promising suppression effects were also evaluated as inhibitors against the mutant forms EGFR^L858R and EGFR^T790M. The 4-aminopyrazolone analogue 9a showed superior anticancer activity against both HepG-2 and MCF-7 cell lines (IC50 = 1.27, 10.80 μM, respectively) and more potent enzymatic inhibition activity against EGFR^WT and its mutant forms EGFR^L858R and EGFR^T790M than that obtained by erlotinib (IC₅₀ = 0.021, 0.053, 0.081 µM, respectively, IC_50erlotinib; 0.027, 0.069, 0.550 µM, respectively). Finally, the molecular docking study showed good binding patterns of the most active compounds with the prospective target EGFR^WT.     

Virtual screening of B-Raf kinase inhibitors: A combination of pharmacophore modelling,molecular docking, 3D-QSAR model and binding free energy calculation studies

B-Raf kinase has been identified as an important target in recent cancer treatment. In order to discover structurally diverse and novel B-Raf inhibitors (BRIs), a virtual screening of BRIs against ZINC database was performed by using a combination of pharmacophore modelling, molecular docking, 3D-QSAR model and binding free energy (ΔG_bind) calculation studies in this work. After the virtual screening, six promising hit compounds were obtained, which were then tested for inhibitory activities of A375 cell lines. In the result, five hit compounds show good biological activities (IC₅₀ < 50 μM). The present method of virtual screening can be applied to find structurally diverse inhibitors, and the obtained five structurally diverse compounds are expected to develop novel BRIs.     

Synthesis and biological evaluation of substituted indazolyl amide derivatives as S-adenosyl-L-homocysteine hydrolase inhibitors

A series of novel amide derivatives bearing an indazole moiety were synthesized and evaluated for their in vitro S-adenosyl-L-homocysteine hydrolase (SAHase) inhibitory activity. Among these compounds, 8b, 8m, 8r and 8w showed better or similar inhibitory effects compared to the positive control aristeromycin. These results provide a novel lead for the discovery of more potent non-adenosine analogs as SAHase inhibitors.     

Design, synthesis and biological evaluation of novel glucokinase activators

A new series of benzamide derivatives as glucokinase activators(GKAs) were designed and synthesized,and their activation for glucokinase were evaluated by the preliminary glucokinase activity assay.The structure-activity relationship(SAR) is discussed. The result shows that compound 12d and 12h have potent activity reference drug RO-28-1675.     

New indolic non-peptidic HIV protease inhibitors from (S)-glycidol: synthesis and preliminary biological activity

A series of non-peptidic HIV protease inhibitors were synthesized starting from the same optically active precursor, (S)-glycidol. The substrate was easily converted into different indolic sulfonamides or amines by regioselective reactions. The preliminary inhibitory activity was evaluated.     

Ytterbium triflate catalyzed synthesis of β-functionalized indole derivatives

Ytterbium triflate was shown to be effective in promoting the synthesis of substituted indole derivatives starting from indole, aldehydes, and dimethyl malonate by a Yonemitsu-type three component reaction. The whole process was carried out in solvent-free conditions and furnished the desired adducts in 42-67% yield.     

Design,synthesis and biological evaluation of novel 3-phenylpropanamide derivatives with acyl hydrazone units

In this study, a series of 3-phenylpropanamide derivatives with acyl hydrazone units were synthesized and characterized by ¹H NMR, ¹³C NMR and HR MS. And the structure of compound III₃₃ was confirmed by X-ray single crystal. The bioassay results showed that, compounds III₈, III₁₇, III₂₂, and III₃₄ showed excellent inhibition on Xanthomonas oryzae pv. pryzae (Xoo) with EC₅₀ values of 7.1, 8.8, 9.5, and 4.7 μg/mL in vitro. The EC₅₀ values of compounds III₁₂, III₁₄ and III₃₃ against Ralstonia solanacearum (Rs) were 7.6, 7.6 and 7.9 μg/mL, respectively, all lower than the values of thiadiazol copper (TC) was 66.8 μg/mL and bismerthiazol (BT) was 72.4 μg/mL. Compounds III₁₂, III₁₄, III₃₃, and III₃₄ exhibited excellent antibacterial activity of more than 80% against Xanthomonas axonopodis pv. citri (Xac) in vitro. Besides, compounds III₈ (51.4%) and III₃₄ (52.1%) were highly effective against Xoo in vivo, outperforming TC (49.5%) and BT (47.8%). Compounds III₈ (29.8%) and III₃₄ (24.6%) were close to TC (41.7%) and BT (47.8%) in terms of protective efficacy against Xoo in vivo. Meanwhile, some of title compounds also displayed inhibitory effects against phytopathogenic fungi. In a word, this study illustrated that the structures combined with phenylpropane amide derivatives of the acyl hydrazone units could be used as potential antibacterial reagents in the future.     

Amino acid derivatives, VIII [1]: synthesis and antimicrobial evaluation of α-amino acid esters bearing an indole side chain

A series of peptide and dipeptide derivatives conjugated with an indole residue were synthesized. The prepared compounds were tested for antimicrobial activity against two different bacterial and one antifungal species displaying different degrees of antimicrobial activities or inhibitory actions. Correspondence: Adel A.-H. Abdel-Rahman, Department of Chemistry, Faculty of Science, Menoufia University, Shebin El-Koam, Egypt.     

Design,synthesis, and biological evaluation of diarylpyrazole derivatives as antitumor agents targeting microtubules

A new series of novel diarylpyrazole derivatives as microtubule destabilizers were synthesized and evaluated for the anti-proliferative activities. Anti-proliferative assays were performed on the human cervix adenocarcinoma cell line (HeLa) and human gastric adenocarcinoma cell line (SGC-7901), and the compound 9s containing indole ring showed great anti-proliferative activity against HeLa cells with IC₅₀ value of 1.9 ± 0.11 μM. Further biological studies showed that 9s was able to inhibit tubulin polymerization, disrupt the cytoskeleton, block the cell cycle in the G2/M phase, and induce cell apoptosis in a concentration-dependent manner. In addition, the results of molecular docking studies showed that compound 9s could bind tightly to the colchicine binding site of tubulin through hydrogen bonding interaction. These preliminary results recommend that compound 9s is likely to be a microtubule destabilizer that deserves further investigation.     

Design,synthesis and biological evaluation of acylhydrazone derivatives as PI3K inhibitors

Since the PI3K signaling pathway is the most commonly activated in human cancers,inhibition of PI3K is a promising approach to cancer therapy.In this study,a series of 2-methyl-5-nitrobenzeneacylhydrazones were designed and synthesized.All the new derivatives were tested by p110α enzymatic and Rh30 cellular assays.Further enzyme selectivity profiling proved that 6e and 7 were potential selective PI3K inhibitors.     

Design,synthesis and biological evaluation of novel arylpiperazine derivatives on human prostate cancer cell lines

A series of novel arylpiperazine derivatives was synthesized. The in vitro cytotoxic activities of all synthesized compounds against three human prostate cancer cell lines(PC-3, LNCa P, and DU145) were evaluated by a CCK-8 assay. Compounds 8, 10, 13, 17 and 20 exhibited strong cytotoxic activities against the tested cancer cell lines(IC_(50)3 μmol/L). In addition, these compounds exhibited weak cytotoxic effects on human epithelial prostate normal cells WPMY-1. The structure–activity relationship(SAR) of these arylpiperazine derivatives was also discussed based on the obtained experimental data.     

Synthesis and biological evaluation of novel phenothiazine derivatives as non-peptide arginine vasopressin V2 receptor antagonists

A series of novel phenothiazine derivatives was synthesized and tested for arginine vasopressin receptor antagonist activity. They were synthesized as novel arginine vasopressin receptor antagonists from phenothiazine as a scaffold via successive acylation, reduction and acylation reactions. Their structures were characterized by 1HNMR, 13CNMRandHRMS, and biological activitywas evaluated by in vitro and in vivo studies. The in vitro binding assay indicated that several compounds are potent selective V2 receptor antagonists. Compounds with promising binding affinity to V2 receptors were selected to conduct the in vivo diuretic studies on Sprague-Dawley rats. Among them, 1n, 1r, 1t and 1v exhibited excellent diuretic activity, especially 1r and 1v. Therefore, 1r and 1v are potent novelAVP V2receptor antagonist candidates.     

Design,synthesis, and biological evaluation of new ALDH2 activators

Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is an important enzyme response for the metabolism or detoxification of toxic aldehydes, in particular acetaldehyde and 4-hydroxynonenal (4-HNE), which were important risk factors for acute alcoholism and stroke respectively. A special variant ALDH212 with reduced enzymatic activity was carried by a high percentage of East Asians, especially Han Chinese, and that could increase the risk of these diseases further. Therefore, ALDH2 activators had important potential clinical values. N-benzylbenzamide compounds represented by Alda-1 were the only ALDH2-specific activators that have been reported so far. In this study, three new classes of compounds were modified from Alda-1 to improve their water-solubility and then drug-like properties. The results showed that all compounds had increased water solubility and two classes of compounds exhibited good activation activity. Among them, compound I-6 showed the best activity.