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.     

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 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.     

Design,synthesis and biological evaluation of new rhodacyanine analogues as potential antitumor agents

In an attempt to develop potent antitumor agents,new rhodacyanine analogues containing the pyridinium ring（5a-5h）,the isoquinolinium ring（6a-6c） and the quinolinium ring（7a-7e） linked to the rhodanine ring via N-N covalent bond were designed, synthesized and evaluated for antitumor activity against human lung cancer cell line（H460） by MTT assay in vitro.Most of the tested compounds showed enhanced antitumor activity with IC₅₀ values ranging from 0.006 to 9.2 u,mol/L as compared to the lead compound MKT-077.Among them,the most promising compound 7d(IC₅₀ = 0.006μmol/L) was 216.7 times more active than MKT-077(IC₅₀ = 1.3μmol/L).The preliminary structure-activity relationship of the target compounds was discussed.     

Molecular design,synthesis and biological activities of amidines as new ketol-acid reductoisomerase inhibitors

Diamidine （A） was identified in our in vitro bio-assay as a possible inhibitor of ketol-acid reductoisomerase （KARI） from the ACD database search based on the known three-dimensional crystal structure of KARI. An investigation on interaction of A on KARI active sites, led to the design and synthesis of 15 novel monoamidines. Some of those showed better biological activity than A on rice KARI （in vitro） and in greenhouse herbicidal tests （in vivo）. The structure-biological activity relationship was investigated, which provides valuable information to further study of potential KARI inhibitors.     

Design,synthesis and biological evaluation of indole derivatives as novel inhibitors targeting B-Raf kinase

A series of novel indole derivatives were designed and synthesized and their inhibitory activity against B-Raf and HepG2 cell were also described. Among them, compounds 7a and 7b exhibited excellent potency, which showed the potential for further research as lead compounds.     

Design, synthesis and biological activity of cyclohexane-bearing C-glucoside derivatives as SGLT2 inhibitors

Seven cyclohexane-bearing C-glucoside derivatives (7, 9, 12, 13 and 17-19) were designed and synthesized as SGLT2 inhibitors starting from a potent SGLT2 inhibitor we discovered in earlier work, (1S)-1-deoxy-1-[4-methoxy-3-(trans-n-propylcyclohexyl)methylphenyl]-D-glucose (1). The in vitro and in vivo biological activities were evaluated by hSGLT2/hSGLT1 inhibition and urinary glucose excretion (UGE), respectively. Among the synthesized compounds 12, the 6-deoxy derivative of 1 was the most active and selective SGLT2 inhibitor (IC50 = 1.4 nmol/L against hSGLT2; selectivity = 1576). Compound 12 was a potent SGLT2 inhibitor, which could induce more urinary glucose than 1 and dapagliflozin in UGE.     

Design synthesis and biological evaluation of 3-substituted triazole derivatives

Based on the active site of lanosterol 14α-demethylase of azole antifungal agents,sixteen 1-(1H-1,2,4-triazole-1-yl)- 2-(2,4- difluorophenyl)-3-(N-n-butyl-N-1-substitutedbenzyl-4-methylene-1H-1,2,3-triazole)-2-propanols have been designed,synthesized and evaluated as antifungal agents.Results of preliminary antifungal tests against eight human pathogenic fungi in vitro showed that some of the compounds exhibited excellent activities with broad spectrum.     

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.     

Synthesis and biological activity of novel 2-methyl-4-trifluoromethyl-thiazole-5-carboxamide derivatives

Nine novel 2-methyl-4-trifluoromethylthiazole-5-carboxamide derivatives were designed and synthesized utilizing ethyl 4,4,4-trifluoroacetoacetate as a starting material. Subsequently, the biological activity of the compounds was evaluated in the greenhouse. Results indicated that all of the compounds have some fungicidal and insecticidal activity but no herbicidal activity. Compound 1 has fungicidal activity with 90% control of tomato late blight at 375 g ai/ha, while two compounds 2F and 2H show insecticidal activity with 80 and 100% control, respectively, against potato leafhopper at 600 g ai/ha.     

Synthesis and biological evaluation of 3-amino-2-pyrones as selective cyclooxygenase-1 (COX-1) inhibitors

A group of 3-amino-2-pyrones were synthesized and their biological activities were evaluated for inhibiting cyclooxygenase（COX） activity.This study has led to the identification of COX-1-selective inhibitors.Among the tested compounds,the compound 5j exhibited the most potent COX-1 inhibitory activity(IC₅₀ = 19.32μg/mL) and COX-1 selectivity index（SI = 41.98）.     

Design,synthesis and biological evaluation of sulfenimine cephalosporin sulfoxides as β-lactamase inhibitors

A series of sulfenimine cephalosporin sulfoxide derivatives(7a–v) were designed, synthesized and evaluated for their inhibitory activity against TEM-1 and cephalosporinase in cell-free systems. Some of the tested compounds showed enhanced inhibitory activity against class C b-lactamase cephalosporinase compared with the tazobactam. The most promising compounds 7c and 7n(IC50= 7.6 and8.6 mmol/L, respectively) were further investigated in combination with cefradine against a variety of clinical isolated b-lactamase-producing bacterial strains.     

Synthesis and biological evaluation of novel steroid-linked nitrogen mustards

Two novel steroid-linked nitrogen mustard conjugates 1a and 1b were synthesized by using estrogenic acid 4 coupled with aniline mustard 8 and phenol mustard 13 in an esterification or amidation procedure. Preliminary cytotoxic screening on cancer cell lines in vitro showed that, the steroid-ester linked nitrogen mustard conjugate la exhibited obvious increasing of activities.     

Synthesis and microbiological evaluation of several benzocaine derivatives

Starting from benzocaine, a well-known anaesthetic, ten derivatives were synthesized and characterized by UV–vis, IR, NMR, and elemental analysis. Most of the compounds contain residues with recognized biological activity, like nicotinic acid (vitamin B3 or PP), biotin (vitamin B7 or H), lipoic acid (thioctic acid), adamantine, as well as other residues of crown-ether type, benzofurazane, naphtylurea, di- and tri-nitrobenzene, and a nitroxide radical. The biological evaluation of the obtained compounds included hydrophobicity (lipophobicity) assay, total antioxidant and microbiological activity tests.     

Design,synthesis, and characterization of some new benzimidazole derivatives and biological evaluation

A new series of benzimidazole derivatives ( 1-15 ) containing 1,2,4-triazole, 1,3,4-thiadiazole, 1,3,4-oxadiazole, and thiazolidinon rings have been synthesized. All new synthesized benzimidazole compounds were confirmed by ¹H NMR, ¹³C NMR spectra, and LC-MS, and they were examined for their antioxidant and antimicrobial activities. Compounds 7 and 1 showed the highest and the lowest antioxidant activities, respectively. The lowest minimum inhibition concentration value found in compound 5 against Enterobacter aerogenes.     

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.     

Design,synthesis, computational and biological evaluation of new benzodiazepines as CNS agents

Two series of new benzodiazepines were synthesized and the target compounds (E1-10 and G1-10) were evaluated for antianxiety and skeletal muscle relaxant activity as CNS agents in albino mice. The chemical structures of the compounds were confirmed on the basis of their TLC, IR, ¹H NMR and ¹³C NMR analysis. In computational studies, the physicochemical similarity of the target compounds was assessed by calculating from a set of physicochemical properties using software programs and test compounds demonstrated moderate physiochemical similarity with respect to diazepam. Log P values of the target compounds indicates good penetration to CNS. Molecular docking studies revealed that the target compounds correctly dock into the binding pocket of the GABA_A receptor, while their bioavailability/drug-likeness was predicted to be acceptable but requires future optimization. The test compounds (E1-10 and G1-10) were screened for antianxiety and skeletal muscle relaxant activity using Elevated plus maze and Rotarod method respectively. Among them, the compounds E10 and G7 showed maximum potency as CNS agents.     

Design, synthesis and biological evaluation of new oxazines with potential antiparasitic activity

A series of new oxazines with potential antiparasitic activity was prepared using Diels-Alder reactions, based on terpenes derived from eucarvone as dienes and nitrosoarenes with different electronic characteristics as dienophiles. The biological activity was evaluated with in vitro assays against Plasmodium falciparum, Trypanosoma cruzi and Trypanosoma brucei rhodesiense. Some of these oxazines have activities in the 20-50 μM range, and may be leaders for the development of novel antiparasitic drugs with improved pharmacological properties.     

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.