Design and synthesis of biphenyl derivatives as mushroom tyrosinase inhibitors

Two new series of biphenyls, analogs of aglycone of natural product fortuneanoside E, were prepared using Suzuki–Miyaura cross-coupling and selective magnesium iodide demethylation/debenzylation, and their mushroom tyrosinase inhibitory activity was evaluated. Most of the 4-hydroxy-3,5-dimethoxyphenyl biphenyl compounds (series II, 20–36) were in general more active than 3,4,5-trimethoxyphenyl biphenyl compounds (series I, 1–19). Structure–activity relationships study showed that monosaccharide substituents, such as glucose, were not necessary and the presence of 4-hydroxy-3,5-dimethoxyphenyl moiety was crucial for inhibitory activity. Among the compounds synthesised, compound 21 (IC₅₀ = 0.02 mM) was found to be the most active one, which exhibited an activity that was 7 times higher than that of fortuneanoside E (IC₅₀ = 0.14 mM) and 10 times higher than that of arbutin (IC₅₀ = 0.21 mM), known as potent tyrosinase inhibitors. The inhibition kinetics analyzed by Lineweaver–Burk plots revealed that compound 21 was a competitive inhibitor (K_i = 0.015 mM).     

Design,synthesis and antibacterial activity studies of thiazole derivatives as potent ecKAS III inhibitors

Two series of thiazole derivatives containing amide skeleton were synthesized and developed as potent Escherichia coli β-ketoacyl-(acyl-carrier-protein) synthase III (ecKAS III) inhibitors. All the 24 new synthesized compounds were assayed for antibacterial activity against the respective Gram-negative and Gram-positive bacterial strains, including E. coli, Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus. In which, 10 compounds with broad-spectrum antibacterial activities were further tested for their ecKAS III inhibitory activity. Last, we have successfully found that compound 4e showed both the promising broad antibacterial activity with MIC of 1.56–6.25 μg/mL against the representative bacterial stains, and also processed the most potent ecKAS III inhibitory activity with IC₅₀ of 5.3 μM. In addition, docking simulation also carried out in this study to give a potent prediction binding mode between the small molecule and ecKAS III (PDB code: 1hnj) protein.     

Design and synthesis of eugenol derivatives, as potent 15-lipoxygenase inhibitors

A group of 4-allyl-2-methoxyphenol (eugenol) esters were designed, synthesized, and evaluated as potential inhibitors of soybean 15-lipoxygenase (SLO). Compounds 4c, 4d 4f, 4p, and 4q showed the best IC(50) in SLO inhibition (IC(50)=1.7, 2.3, 2.1, 2.2, and 0.017microM, respectively). All compounds were docked into SLO active site and showed that allyl group of compounds is oriented toward the iron atom in the active site of SLO. It is assumed that lipophilic interaction of ligand-enzyme would be in charge of inhibiting the enzyme activity. The selectivity of eugenol derivatives in inhibiting 15-HLOb was also compared with 15-HLOa by molecular modeling and multiple alignment techniques.     

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.     

Design,synthesis and molecular modelling studies of some pyrazole derivatives as carbonic anhydrase inhibitors

Abstract

In this study, newly synthesised compounds 6, 8, 10 and other compounds (1–5, 7 and 9) and their inhibitory properties against the human isoforms hCA I and hCA II were reported for the first time. Compounds 1–10 showed effective inhibition profiles with K _I values in the range of 5.13–16.9?nM for hCA I and of 11.77–67.39?nM against hCA II, respectively. Molecular docking studies were also performed with Glide XP to get insight into the inhibitory activity and to evaluate the binding modes of the synthesised compounds to hCA I and II. More rigorous binding energy calculations using MM-GBSA protocol which agreed well with observed activities were then performed to improve the docking scores. Results of in silico calculations showed that all compounds obey drug likeness properties. The new compounds reported here might be promising lead compounds for the development of new potent inhibitors as alternatives to classical hCA inhibitors.     

Design,synthesis, anticancer evaluation and docking studies of new pyrimidine derivatives as potent thymidylate synthase inhibitors

Cancer is a perplexing and challenging problem for researchers. In this study, a series of 6-aryl-5-cyano-pyrimidine derivatives were designed, synthesized and evaluated for their anticancer activity against HePG-2, MCF-7 and HCT-116 cell lines. Compounds 2, 3d, 4a-c, 5, 8 and 12 displayed high anticancer activity, comparable to that of 5-fluorouracil. Additionally, those compounds with effective anticancer activity were further assessed for their ability to inhibit thymidylate synthase (TS) enzyme. All the tested compounds demonstrated a marked TS inhibitory activity (33.66–74.98%), with IC₅₀ ranging from 3.89 to 15.74 nM. Moreover, apoptosis studies were conducted on the most potent compound 8, to evaluate its proapoptotic potential. Interestingly, compound 8 induced the level of active caspase 3, and elevated the Bax/Bcl2 ratio 44 folds in comparison to the control. Finally, a molecular docking study was conducted to detect the probable interaction between the active compounds and the thymidylate synthase active site.     

Synthesis of novel azo-resveratrol,azo-oxyresveratrol and their derivatives as potent tyrosinase inhibitors

Ten azo compounds including azo-resveratrol (5) and azo-oxyresveratrol (9) were synthesized using a modified Curtius rearrangement and diazotization followed by coupling reactions with various phenolic analogs. All synthesized compounds were evaluated for their mushroom tyrosinase inhibitory activity. Compounds 4 and 5 exhibited high tyrosinase inhibitory activity (56.25% and 72.75% at 50 μM, respectively). The results of mushroom tyrosinase inhibition assays indicate that the 4-hydroxyphenyl moiety is essential for high inhibition and that 3,5-dihydroxyphenyl and 3,5-dimethoxyphenyl derivatives are better for tyrosinase inhibition than 2,5-dimethoxyphenyl derivatives. Particularly, introduction of hydroxyl or methoxy group into the 4-hydroxyphenyl moiety diminished or significantly reduced mushroom tryosinase inhibition. Among the synthesized azo compounds, azo-resveratrol (5) showed the most potent mushroom tyrosinase inhibition with an IC₅₀ value of IC₅₀ = 36.28 ± 0.72 μM, comparable to that of resveratrol, a well-known tyrosinase inhibitor.     

Design,synthesis and biological evaluation of anthranilamide derivatives as potent SMO inhibitors

A series of anthranilamide derivatives were designed and synthesized as novel smoothened (SMO) inhibitors based on the SMO inhibitor taladegib (LY2940680), which can also inhibit the SMO-D473H mutant, via a ring-opening strategy. The phthalazine core in LY2940680 was replaced with anthranilamide, which retained the inhibitory activity towards the hedgehog (Hh) signaling pathway as evidenced by a dual luciferase reporter gene assay. Compound 12a displayed the best inhibitory activity against the Hh signaling pathway with IC₅₀ value of 34.09 nM, and exhibited better proliferation inhibitory activity towards the Daoy cell line (IC₅₀ = 0.48 μM) than LY2940680 (IC₅₀ = 0.79 μM).     

1,2,3-Triazole-based kojic acid analogs as potent tyrosinase inhibitors: Design,synthesis and biological evaluation

A series of kojic acid-derived compounds 6a-p bearing aryloxymethyl-1H-1,2,3-triazol-1-yl moiety were designed by modifying primary alcoholic group of kojic acid as tyrosinase inhibitors. The target compounds 6a-p were synthesized via click reaction. All compounds showed very potent anti-tyrosinase activity (IC₅₀s = 0.06–6.80 µM), being superior to reference drug, kojic acid. In particular, the naphthyloxy analogs 6o and 6p were found to be 31–155 times more potent than kojic acid. The metal-binding study of selected compound 6o revealed that the prototype compound possesses metal-chelating ability, particularly with Cu²⁺ ions. The promising compounds 6o and 6p had acceptable safety profile as demonstrated by cytotoxicity assay against melanoma (B16) cell line and Human Foreskin Fibroblast (HFF) cells.     

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 biological evaluation of spiropyrazolopyridone derivatives as potent dengue virus inhibitors

The effective treatment for dengue virus infection continues to be a challenge. We herein reported our continued SAR exploration on the spiropyrazolopyridone scaffold. Introducing different substituents at the 3́- or 5́-site of the pyrazolopyridone core or moving the benzyl chain to the adjacent nitrogen led to a significant loss of potency on DENV-2. While a narrow range of substitutions were tolerated at the para-position of the phenyl ring, di-substitution on the phenyl ring is beneficial for DENV-2 potency and has variable influences on DENV-3 potency depending on the exact compound. Among these molecules, compounds 22 (JMX0376) with 4-chloro-3-fluorobenzyl and 24 (JMX0395) with 2,4-bis(trifluoromethyl)benzyl showed the most potent and broadest inhibitory activities against DENV-1 to −3 with nanomolar to low micromolar EC₅₀ values.     

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.     

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 and synthesis of thiourea derivatives with sulfur-containing heterocyclic scaffolds as potential tyrosinase inhibitors

Tyrosinase is a key enzyme during the production of melanins in plants and animals. A class of novel N-aryl-N′-substituted phenylthiourea derivatives (3a–i, 6a–k) were designed, synthesized and their inhibitory effects on the diphenolase activity of mushroom tyrosinase were evaluated. The results showed some 4,5,6,7-tetrahydro-2-[[(phenylamino)thioxomethyl]amino]-benzo[b]thiophene-3-carboxylic acid derivatives (3a–i) exhibited moderate inhibitory potency on diphenolase activity of tyrosinase. When the scaffold of 4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid was replaced with 2-(1,3,4-thiadiazol-2-yl)thio acetic acid, the inhibitory activity of compounds (6a–k) against tyrosinase was improved obviously; especially, the inhibitory activity of compound 6h (IC₅₀ = 6.13 μM) is significantly higher than kojic acid (IC₅₀ = 33.3 μM). Moreover, the analysis on inhibition mechanism revealed that compound 6h might plays the role as a noncompetitive inhibitor.     

Lysine derivatives as potent HIV protease inhibitors. Discovery, synthesis and structure-activity relationship studies

A screening assay program on HIV-protease was carried out on more than fifty commercially available N-protected amino acids and has revealed that those with a long side chain such as lysine, ornithine and arginine exhibited significant inhibition of HIV protease enzyme. The presence of an Fmoc group was found to be essential to obtain micromolar inhibitors and the addition of an alkyl group at the Nalpha-position resulted in the discovery of the lead compound 11 displaying a 5 nM inhibition constant. Although this new inhibitor series is not categorized among those mimicking the substrate with a non-hydrolyzable transition-state isoster, it was found very specific to inhibit HIV protease enzyme in comparison to the mammalian aspartyl proteases pepsin, renin and cathepsin. Furthermore, these inhibitors did not show any cytotoxicity at a concentration below 75 microM.     

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.     

Design, synthesis and docking studies on benzamide derivatives as histone deacetylase inhibitors

A series of benzamide derivatives including two scaffolds were designed and synthesized as potential histone deacetylase inhibitors. Most of synthesized compounds showed moderate enzymatic potency at the same order of magnitude, and compound 12b possessed better potency to the positive control (3.8 μM vs 13.0 μM). It also showed a 50-fold increase in vitro anticancer activity against DU-145 cell-lines. Molecular docking studies were carried out and used to explain the structure-activity relationships observed in vitro. Then we found that the cavity surrounded by ASP104, HIS33, PRO34 and PHE155 may be crucial for the inhibitors’ activity. The docking results provide some useful information for future design of more potent inhibitors.     

Indole derivatives as potent inhibitors of 5-lipoxygenase: design, synthesis, biological evaluation, and molecular modeling

A series of novel indole derivatives was designed, synthesized and evaluated by cell-based assays for their inhibitory activities against 5-LOX in rat peritoneal leukocytes. Most of them (30 out of 35) showed an inhibitory potency higher than the initial screening hit 1a (IC(50)=74 microM). Selected compounds for concentration-response studies showed prominent inhibitory activities with IC(50) values ranging from 0.74 microM to 3.17 microM. Four compounds (1m, 1s, 4a, and 6a) exhibited the most potent inhibitory activity compared to that of the reference drug (Zileuton), with IC(50) values less than 1 microM. Molecular modeling studies for compounds 1a, 3a, 4a, and 6a were also presented. The excellent in vitro activities of this class of compounds may possess potential for the treatment of LT-related diseases.     

Design,synthesis and SAR studies of 4-allyoxyaniline amides as potent 15-lipoxygensae inhibitors

A group of 4-allyloxyaniline amides 5a–o were designed, synthesized and evaluated as potential inhibitors of soybean 15-lipoxygenase (SLO) on the basis of eugenol and esteragol structures. Compound 5e showed the best IC₅₀ in SLO inhibition (IC₅₀ = 0.67 ± 0.06 μM). All compounds were docked in SLO active site retrieved from RCSB Protein Data Bank (PDB entry: 1IK3) and showed that allyloxy group of compounds is oriented towards the Fe³⁺-OH moiety in the active site of enzyme and fixed by hydrogen bonding with two conserved His⁵¹³ and Gln⁷¹⁶. It is resulted that molecular volume of the amide moiety would be a major factor in inhibitory potency variation of the synthetic amides, where the hydrogen bonding of the amide group could also involve in the activity of the inhibitors.