Design,synthesis and antibacterial activities of thiouracil derivatives containing acyl thiourea as SecA inhibitors

A series of novel thiouracil derivatives containing an acyl thiourea moiety (7a–7x) have been synthesized by structural modification of a lead SecA inhibitor, 2. All the compounds have been evaluated for their antibacterial activities against Bacillus amyloliquefaciens, Staphylococcus aureus, and Bacillus subtilis. Compounds 7c, 7m, 7u, 7v exhibited promising activities against above bacteria. Such four compounds were further tested for their inhibitory activity against SecA ATPase, and the results showed that compounds 7c and 7u had higher inhibitory activities than that of compound 2. Molecular docking work suggests that compound 7u might bind at a pocket close to the ATPase ATP-binding domain.     

Design,synthesis and evaluation of novel pyrazolo-pyrimido[4,5-d]pyrimidine derivatives as potent antibacterial and biofilm inhibitors

An efficient four-component reaction of 6-amino-1,3-dimethyluracil, N,N-dimethylformamide dimethylacetal, 1-phenyl-3-(4-substituted-phenyl)-4-formyl-1H-pyrazoles and aromatic amines was conducted in the presence of [Bmim]FeCl₄ ionic liquid as a promoting medium. This strategy provided a convenient route without any additional catalyst or metal salt under mild conditions. All the synthesized pyrazolo-pyrimido[4,5-d]pyrimidines derivatives were evaluated for their antibacterial, minimum bactericidal concentration (MBC), biofilm inhibition, intracellular ROS accumulation and protein leakage activities. The results revealed that among all the screened derivatives, the compounds 5c, 5i, 5l and 5m were quite promising with MIC values ranging between 3.9 and 15.6 μg/mL, while the MBC values were 2-fold the antibacterial activity values. The biofilm inhibition activity revealed that the compounds 5l and 5 m exhibited promising activity with IC₅₀ values ranging between 1.8 and 8.2 μg/mL. It was observed that at a concentration of 0.5 μg/mL, the compound 5l treated biofilms of Micrococcus luteus showed increased levels of intracellular ROS accumulation. Further, the protein leakage study revealed that the Micrococcus luteus cells treated with compound 5l caused membrane permeability which resulted in protein leakage and subsequent bacterial cell death.     

Design,synthesis and molecular docking of amide and urea derivatives as Escherichia coli PDHc-E1 inhibitors

By targeting the ThDP binding site of Escherichia coli PDHc-E1, two new ‘open-chain’ classes of E. coli PDHc-E1 inhibitors, amide and urea derivatives, were designed, synthesized, and evaluated. The amide derivatives of compound 6d, with 4-NO₂ in the benzene ring, showed the most potent inhibition of E. coli PDHc-E1. The urea derivatives displayed more potent inhibitory activity than the corresponding amide derivatives with the same substituent. Molecular docking studies confirmed that the urea derivatives have more potency due to the two hydrogen bonds formed by two NH of urea with Glu522. The docking results also indicate it might help us to design more efficient PDHc-E1 inhibitors that could interact with Glu522.     

Design, synthesis and preliminary evaluation of new cinnamoyl pyrrolidine derivatives as potent gelatinase inhibitors

A series of new cinnamoyl pyrrolidine derivatives have been synthesized based on the l-hydroxyproline scaffold and inhibiting activities on gelatinase (MMP-2 and -9) and APN were tested. Structure–activity relationship studies showed that the side chain with aromatic ring at C4in pyrrolidine ring showed better inhibitory activities on gelatinase than aliphatic side chain. Most compounds exhibited poor activities on APN compared with MMP-2. Within this series, three compounds, A8, B9 and C10, have the good potency (IC₅₀ = 5.2–9.7 nM) and could be used as lead compounds in the future.     

Novel amide derivatives containing 1,3,4-thiadiazole moiety: Design,synthesis, nematocidal and antibacterial activities

A series of novel amide derivatives containing 1,3,4-thiadiazole moiety were synthesized and their bioactivities were evaluated. The compound 34 exhibited good nematocidal activities against Meloidogyne incognita in vitro and in vivo, the LC₅₀ value and control effect were 6.5?mg/L and 83.3%, respectively. Meanwhile, it exhibited exciting antibacterial activities against Xanthomonas oryzae pv. oryzae, Xanthomonas campestris pv. citri, and Ralstonia solanacearum, the EC₅₀ values were 0.4, 6.7 and 5.1?mg/L, respectively, which were better than positive controls. The curative and protection activities under the greenhouse conditions of compound 34 against rice bacterial blight were 47.9 and 55.8%, respectively. The structure-activity relationship were analyzed in detail.     

Synthesis and biological evaluation of thiazole derivatives as novel USP7 inhibitors

Herpesvirus-associated Ubiquitin-Specific Protease (HAUSP, also called USP7) interacts with and stabilizes Mdm2, and represents one of the first examples that deubiquitinases oncogenic proteins. USP7 has been regarded as a potential drug target for cancer therapy. Inhibitors of USP7 have been recently shown to suppress tumor cell growth in vitro and in vivo. Based on leading USP7 inhibitors P5091 and P22077, we designed and synthesized a series of thiazole derivatives. The results of in vitro assays showed that the thiazole compounds exhibited low micromolar inhibition activity against both USP7 enzyme and cancer cell lines. The compounds induced cell death in a p53-dependent and p53-independent manner. Taken together, this study may provide thiazole compounds as a new class of USP7 inhibitors.     

Design,synthesis and biological evaluation of novel oseltamivir derivatives as potent neuraminidase inhibitors

Neuraminidase (NA) is one of the particular potential targets for novel antiviral therapy. In this work, a series of neuraminidase inhibitors with the cyclohexene scaffold were studied based upon the combination of 3D-QSAR, molecular docking, and molecular dynamics techniques. The results indicate that the built 3D-QSAR models yield reliable statistical information: the correlation coefficient (r²) and cross-validation coefficient (q²) of CoMFA (comparative molecular field analysis) are 0.992 and 0.819; the r² and q² of CoMSIA (comparative molecular similarity analysis) are 0.992 and 0.863, respectively. Molecular docking and MD simulations were conducted to confirm the detailed binding mode of enzyme-inhibitor system. The new NA inhibitors had been designed, synthesized, and their inhibitory activities against group-1 neuraminidase were determined. One agent displayed excellent neuraminidase inhibition, with IC₅₀ value of 39.6?μM against NA, while IC₅₀ value for oseltamivir is 61.1?μM. This compound may be further investigated for the treatment of infection by the new type influenza virus.     

Design,synthesis and biological evaluation of novel zanamivir derivatives as potent neuraminidase inhibitors

Neuraminidase (NA) is an important antiviral drug target. Zanamivir is one of the most potent NA inhibitors. In this paper, a series of zanamivir derivatives as potential NA inhibitors were studied by combination of molecular modeling techniques including 3D-QSAR, molecular docking, and molecular dynamics (MD) simulation. The results show that the best CoMFA (comparative molecular field analysis) model has q²?=?0.728 and r²?=?0.988, and the best CoMSIA (comparative molecular similarity indices analysis) model has q²?=?0.750 and r²?=?0.981, respectively. The built 3D-QSAR models show significant statistical quality and excellent predictive ability. Seven new NA inhibitors were designed and predicted. 20?ns of MD simulations were carried out and their binding free energies were calculated. Two designed compounds were selected to be synthesized and biologically evaluated by NA inhibition and virus inhibition assays. One compound (IC₅₀?=?0.670?µM, SI?>?149) exhibits excellent antiviral activity against A/WSN/33 H1N1, which is superior to the reference drug zanamivir (IC₅₀?=?0.873?µM, SI?>?115). The theoretical and experimental results may provide reference for development of new anti-influenza drugs.     

Design,synthesis and antimicrobial activities evaluation of Schiff base derived from secnidazole derivatives as potential FabH inhibitors

FabH, β-ketoacyl-acyl carrier protein (ACP) synthase III, is critically important to the initiation of fatty acid biosynthesis and is highly conserved among Gram-positive and Gram-negative bacteria. A series of novel secnidazole derivatives (1–20) were synthesized and fully characterized by spectroscopic methods and elemental analysis. Among these compounds, 6, 8, 11, 13, 14, 16–20 were reported for the first time. These compounds were tested for antibacterial activities against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus. The compounds inhibitory assay and docking simulation indicated that compound 20 (E)-2-(2-methyl-5-nitro-1H-imidazol-1-yl)-N′-(3,4,5-trimethylbenzylidene)acetohydrazide with MIC of 3.13–6.25 μg/mL against the tested bacterial strains was a potent inhibitor of Escherichia coli FabH.     

Design, synthesis and evaluation of flavonoid derivatives as potent AChE inhibitors

A new series of flavonoid derivatives have been designed, synthesized and evaluated as potent AChE inhibitors. Most of them showed more potent inhibitory activities to AChE than rivastigmine. The most potent inhibitor isoflavone derivative 10d inhibit AChE with a IC₅₀ of 4 nM and showed high BChE/AChE inhibition ratio (4575-fold), superior to donepezil (IC₅₀ = 12 nM, 389-fold). Molecular docking studies were also performed to explore the detailed interaction with AChE.     

In vitro and in silico evaluation of new thiazole compounds as monoamine oxidase inhibitors

New twenty compounds bearing thiazole ring (3a-3t) were designed and synthesized as monoamine oxidase (MAO) inhibitors. The fluorometric enzyme inhibition assay was used to determine the biological effects of synthesized compounds. Most of them showed remarkable inhibitory activity against both MAO-A and MAO-B. By comparing their IC₅₀ values, it can be seen that active derivatives displayed generally selectivity on MAO-B enzyme. Compounds 3j and 3t, which bear dihydroxy moiety at the 3rd and 4th position of phenyl ring, were the most active derivatives in the series against both isoenzymes. Compounds 3j and 3t showed significant inhibition profile on MAO-A with the IC₅₀ values of 0.134 ± 0.004 µM and 0.123 ± 0.005 µM, respectively, while they performed selectivity against MAO-B with the IC₅₀ values of 0.027 ± 0.001 µM and 0.025 ± 0.001 µM, respectively. Also, docking studies about these compounds were carried out to evaluate their binding modes on the active regions of MAO-A and MAO-B.     

Design,synthesis, and biological activity of novel tetrahydropyrazolopyridone derivatives as FXa inhibitors with potent anticoagulant activity

A series of novel tetrahydropyrazolopyridone derivatives containing 1,3,4-triazole, triazolylmethyl, and partially saturated heterocyclic moieties as P2 binding element was designed, synthesized, and evaluated in vitro for anticoagulant activity in human and rabbit plasma. All compounds showed moderate to significant potency, and compounds 15b, 15c, 20b, 20c, and 22b were further examined for their inhibitory activity against human FXa in vitro. While compounds 15c and 22b were tested for rat venous thrombosis in vivo. The most promising compound 15c, with an IC₅₀ (FXa) value of 0.14 μM and 98% inhibition rate, warranted further investigation as an FXa inhibitor.     

Design,synthesis and pharmacological evaluation of chalcone derivatives as acetylcholinesterase inhibitors

A novel series of chalcone derivatives (4a–8d) were designed, synthesized, and evaluated for the inhibition activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The log P values of the compounds were shown to range from 1.49 to 2.19, which suggested that they were possible to pass blood brain barriers in vivo. The most promising compound 4a (IC₅₀: 4.68 μmol/L) was 2-fold more potent than Rivastigmine against AChE (IC₅₀: 10.54 μmol/L) and showed a high selectivity for AChE over BuChE (ratio: 4.35). Enzyme kinetic study suggested that the inhibition mechanism of compound 4a was a mixed-type inhibition. Meanwhile, the result of molecular docking showed its potent inhibition of AChE and high selectivity for AChE over BuChE.     

Design,synthesis and biological evaluation of novel thiazole derivatives as potent FabH inhibitors

Fatty acid biosynthesis is essential for bacterial survival. Components of this biosynthetic pathway have been identified as attractive targets for the development of new antibacterial agents. FabH, β-ketoacyl-acyl carrier protein (ACP) synthase III, is a particularly attractive target, since it is central to the initiation of fatty acid biosynthesis and is highly conserved among Gram positive and negative bacteria. Three series of Schiff bases containing thiazole template were synthesized and developed as potent inhibitors of FabH. This inhibitor class demonstrates strong antibacterial activity. Escherichia coli FabH inhibitory assay and docking simulation indicated that the compounds 11 and 18 were potent inhibitors of E. coli FabH.     

New betulinic acid derivatives as potent proteasome inhibitors

In this study, 22 new betulinic acid (BA) derivatives were synthesized and tested for their inhibition of the chymotrypsin-like activity of 20S proteasome. From the SAR study, we concluded that the C-3 and C-30 positions are the pharmacophores for increasing the proteasome inhibition effects, and larger lipophilic or aromatic side chains are favored at these positions. Among the BA derivatives tested, compounds 13, 20, and 21 showed the best proteasome inhibition activity with IC(50) values of 1.42, 1.56, and 1.80 μM, respectively, which are three to fourfold more potent than the proteasome inhibition controls LLM-F and lactacystin.     

Design, synthesis and antibacterial activity of 3-methylenepyrrolidine formyl hydroxyamino derivatives as novel peptide deformylase inhibitors

The synthesis and antibacterial activity of 3-methylenepyrrolidine formyl hydroxyamino derivatives are reported. The antibacterial activities of these derivatives were evaluated to discover SAR at P^1′ and P^3′ positions, and most of these derivatives exhibit better in vitro antibacterial activity than existing drugs against drug-resistant clinical isolates including MRSA, PRSP, and Haemophilus influenzae.     

Novel thiobarbiturates as potent urease inhibitors with potential antibacterial activity: Design,synthesis, radiolabeling and biodistribution study

Urease enzyme is a virulence factor that helps in colonization and maintenance of highly pathogenic bacteria in human. Hence, the inhibition of urease enzymes is well-established to be a promising approach for preventing deleterious effects of ureolytic bacterial infections. In this work, novel thiobarbiturate derivatives were synthesized and evaluated for their urease inhibitory activity. All tested compounds effectively inhibited the activity of urease enzyme. Compounds 1, 2a, 2b, 4 and 9 displayed remarkable anti-urease activity (IC₅₀ = 8.21–16.95 μM) superior to that of thiourea reference standard (IC₅₀ = 20.04 μM). Moreover, compounds 3a, 3g, 5 and 8 were equipotent to thiourea. Among the tested compounds, morpholine derivative 4 (IC₅₀ = 8.21 µM) was the most potent one, showing 2.5 folds the activity of thiourea. In addition, the antibacterial activity of the synthesized compounds was estimated against both standard strains and clinical isolates of urease producing bacteria. Compound 4 explored the highest potency exceeding that of cephalexin reference drug. Moreover, biodistribution study using radiolabeling approach revealed a remarked uptake of ^99mTc-compound 4 into infection induced in mice. Furthermore, a molecular docking analysis revealed proper orientation of title compounds into the urease active site rationalizing their potent anti-urease activity.     

Design,synthesis and biological evaluation of pyrimidine-based derivatives as VEGFR-2 tyrosine kinase inhibitors

Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in tumor angiogenesis, and inhibition of the VEGFR-2 signaling pathway has already become an attractive approach for cancer therapy. In this study, a novel pyrimidine-based derivative 7j was designed as lead compound, and three series of potent VEGFR-2 inhibitors were synthesized and biologically evaluated against A549 and HepG2 cell lines. Compounds 7d, 9s and 13n exhibited superior inhibitory activities against A549 cell with IC₅₀ ranged from 9.19 to 13.17 μM and HepG2 cell with IC₅₀ ranged from 11.94 to 18.21 μM compared to those of Pazopanib (IC₅₀ = 21.18 and 36.66 μM). In addition, molecular docking study was performed to investigate the binding capacity and binding mode between target compounds and VEGFR-2.