Hydroxycoumarins as selective MAO-B inhibitors

A series of 3-aryl-4-hydroxycoumarin derivatives was synthesized with the aim to find out the structural features for the MAO inhibitory activity and selectivity. Methoxy and/or chloro substituents were introduced in the 3-phenyl ring, whereas the position 6 in the coumarin moiety was not substituted or substituted with a methyl group or a chloro atom due to their different electronic, steric and/or lipophilic properties. Most of the synthesized compounds presented MAO-B inhibitory activity. The presence of methoxy and chloro groups, respectively in the para and meta positions of the 3-phenyl ring, have an important influence on the inhibitory activity. Moreover, the presence of a chloro atom in the six position of the moiety (compound 7) improved the inhibitor activity as well as its selectivity against MAO-B compared with iproniazide, used as reference compound. Docking experiments were carried out to understand which are the most energetically preferred orientations adopted by compounds 5, 6 and 7 inside the MAO-B binding pocket.     

Synthesis and PTP1B inhibition of 1,2-naphthoquinone derivatives as potent anti-diabetic agents

A new series of 1,2-naphthoquinone derivatives was synthesized by various synthetic methods and evaluated for their ability to inhibit protein tyrosine phosphatase 1B (PTP1B). 1,2-Naphthoquinone derivatives with substituent at R(4) position showed submicromolar inhibitory activity, and compound 24 demonstrated 10- to 60-fold selectivity against the tested phosphatases. Also, several 4-aryl-1,2-naphthoquinone derivatives with substituents at R(3), R(6), R(7), or/and R(8) showed submicromolar inhibitory activity and good plasma stability.     

Synthesis and in vitro activity of novel isoxazolyl tetrahydropyridinyl oxazolidinone antibacterial agents

A series of isoxazolyl tetrahydropyridinyl oxazolidinones with various substituents at the 3-position of the isoxazole ring have been synthesized and their in vitro antibacterial activities (MIC) were evaluated against several Gram-positive strains including the resistant strains of Staphyloccus and Enterococcus, such as MRSA and VRE. One of the most potent compounds synthesized, 4f, showed comparable or better activity against selected bacterial strains than those of linezolid and vancomycin.     

Synthesis and biological evaluation of 1,3-diphenylprop-2-en-1-ones possessing a methanesulfonamido or an azido pharmacophore as cyclooxygenase-1/-2 inhibitors

A group of (E)-1,3-diphenylprop-2-en-1-one derivatives (chalcones) possessing a MeSO(2)NH, or N(3), COX-2 pharmacophore at the para-position of the C-1 phenyl ring were synthesized using a facile stereoselective Claisen-Schmidt condensation reaction. In vitro COX-1/COX-2 structure-activity relationships were determined by varying the substituents on the C-3 phenyl ring (4-H, 4-Me, 4-F, and 4-OMe). Among the 1,3-diphenylprop-2-en-1-ones possessing a C-1 para-MeSO(2)NH COX-2 pharmacophore, (E)-1-(4-methanesulfonamidophenyl)-3-(4-methylphenyl)prop-2-en-1-one (7b) was identified as a selective COX-2 inhibitor (COX-2 IC(50)=1.0 microM; selectivity index >100) that was less potent than the reference drug rofecoxib (COX-2 IC(50)=0.50 microM; SI>200). The corresponding 1,3-diphenylprop-2-en-1-one analogue possessing a C-1 para-N(3) COX-2 pharmacophore, (E)-1-(4-azidophenyl)-3-(4-methylphenyl)prop-2-en-1-one (7f), exhibited potent and selective COX-2 inhibition (COX-1 IC(50)=22.2 microM; COX-2 IC(50)=0.3 microM; SI=60). A molecular modeling study where 7b and 7f were docked in the binding site of COX-2 showed that the p-MeSO(2)NH and N(3) substituents on the C-1 phenyl ring are oriented in the vicinity of the COX-2 secondary pocket (His90, Arg513, Phe518, and Val523). The structure-activity data acquired indicate that the propenone moiety constitutes a suitable scaffold to design new acyclic 1,3-diphenylprop-2-en-1-ones with selective COX-1 or COX-2 inhibitory activity.     

Synthesis and biological evaluation of novel T-type Ca2+ channel blockers

A small molecule library of piperazinylalkylisoxazole derivatives containing about 600 compounds was designed, synthesized and evaluated for blocking effects on T-type Ca(2+) channel. Several ligands were identified to possess high inhibitory activity against the T-type Ca(2+) channel. The compound 21 with trifluoromethyl substituents at C(3)-position of phenyl group (R(1)) and C(2)-position of phenyl group (R(2)) showed the highest inhibitory activity with IC(50) value of 1.02 microM, which is comparable to that of mibefradil.     

Synthesis and antiviral activity of a new series of 4-isothiazolecarbonitriles

A series of 4-isothiazolecarbonitriles was synthesized and screened for in vitro antiviral activity. The effect of various substituents on the phenyl ring, as well as the substitution of the phenyl for other aromatic and heteroaromatic rings, was examined to establish the requirements for optimum activity. The most active member of the series, 3-methylthio-5-phenyl-4-isothiazolecarbonitrile, exhibited a high level of activity against enteroviruses polio 1 and ECHO 9. Preliminary studies on its mechanism of action indicated that this compound had an effect on an early event in the replication of poliovirus type 1.     

Antitumor dinuclear platinum(II) complexes derived from a novel chiral ligand

A new chiral ligand, 2-(((1R,2R)-2-aminocyclohexyl)amino)acetic acid (HL), was designed and synthesized to prepare a series of novel dinuclear platinum(II) complexes with dicarboxylates or sulfate as bridges. The evaluation of these metal complexes in vitro cytotoxicity against human HCT-116, MCF-7 and HepG-2 cell lines were made. All compounds showed antitumor activity to HCT-116 and MCF-7. Particularly, compounds M3 and M5 not only exhibited better activity than carboplatin against MCF-7 and HepG-2, but also showed very close activity to oxaliplatin against HCT-116.     

Novel 3-(2-adamantyl)pyrrolidines with potent activity against influenza A virus-identification of aminoadamantane derivatives bearing two pharmacophoric amine groups

The 3-(2-adamantyl)pyrrolidines 8a-g, 14 were synthesized and evaluated for activity against influenza A virus. The parent N-H compound 14 was several times more active than amantadine against H(2)N(2) and H(3)N(2) influenza A virus. The combined use of NMR spectroscopy and computational chemistry showed that the conformation around the pyrrolidine-adamantyl carbon-carbon bond is trans and the pyrrolidine heterocycle has an envelope conformation with C-2 out of the plane of the other ring atoms. N-Dialkylaminoethyl substitution of compound 14 resulted in the potent diamine analogues 8e,f,g. Interestingly, their lactam amine precursors were also active. Compounds 8e,f,g are the first adamantane derivatives, bearing two amine groups, reported to be active against influenza A virus.     

Heterocyclic rimantadine analogues with antiviral activity

2-(1-Adamantyl)-2-methyl-pyrrolidines 3 and 4, 2-(1-adamantyl)-2-methyl-azetidines 5 and 6, and 2-(1-adamantyl)-2-methyl-aziridines 7 and 8 were synthesized and tested for their antiviral activity against influenza A. Parent molecules 3, 5, and 7 contain the alpha-methyl-1-adamantan-methanamine 2 pharmacophoric moiety (rimantadine). The ring size effect on anti-influenza A activity was investigated. Pyrrolidine 3 was the most potent anti-influenza virus A compound, 9-fold more potent than rimantadine 2, 27-fold more potent than amantadine 1, and 22-fold more potent than ribavirin. Azetidines 5 and 6 were both markedly active against influenza A H2N2 virus, 10- to 20-fold more potent than amantadine. Aziridine 7 was almost devoid of any activity against H2N2 virus but exhibited borderline activity against H3N2 influenza A strain. Thus, it appears that changing the five-, to four- to a three-membered ring results in a drop of activity against influenza A virus.     

Effect of natural and synthetic benzyl benzoates on calmodulin

The present investigation describes the effect of the spasmolytic benzylbenzoates 1-9 from Brickellia veronicifolia on CaM using a functional in vitro enzymatic assay. Bovine brain PDE1 was used as a monitoring enzyme. The most active natural inhibitors of the system CaM-PDE1 were benzyl benzoates 3-5, which inhibited the activity of PDE1 in a concentration-dependent manner. In addition, three series of analogs of compound 4, compounds 10a-32a, were prepared and assayed. The benzyl benzoates from the first series, namely 10a-24a, possess no substituents on ring B but different number and position of hydroxyl or methoxy groups in ring A. The second group (25-32a), on the other hand, possesses an A ring identical to that on compound 4, but different substituents in Ring B. The most active compounds were 14a, 15a and 30a. These compounds were two to six times more potent than chlorpromazine, a well known CaM inhibitor. Benzyl benzoates 14a and 15a have methoxyl groups at C-2/C-4 and C-3/C-4 in ring A, respectively; while 30a, in addition to the methoxyl groups at C-2/C-6 of ring A, hold a benzoyloxy moiety at C-3' of ring B. Kinetic studies revealed that compounds 3, 4, 14a, 15a and 30a behave as competitive CaM antagonists.     

Synthesis and anti-HCV activity evaluation of anilinoquinoline derivatives

Hepatitis C virus (HCV) infection is a main cause of chronic liver disease, leading to liver cirrhosis and hepatocellular carcinoma (HCC). The objective of our research was to develop effective agents against viral replication. Here, we have synthesized a series of anilinoquinoline derivatives. Based on a cell-based HCV replicon system, we observed that 2-(3'-nitroanilino)quinoline (18) exhibited anti-HCV activity with a 50% effective concentration (EC(50)) value of 7μM and a selective index (SI) value of 10. In addition, compound 18 possessed the inhibitory effect on HCV NS3/4A protease activity. Therefore, we concluded that the compound 18 possessed a potent activity against HCV replication and could provide as a new lead compound as anti-HCV inhibitor.     

Novel 2-substituted nitronyl nitroxides as free radical scavengers: synthesis, biological evaluation and structure-activity relationship

To develop more potent small molecules with enhanced free radical scavenger properties, we designed and synthesized a series of nitronyl nitroxide derivatives 4a-h. A lead compound 4f was discovered based on Ach-induced vascorelaxation assay. Further chemical modification based on this scaffold provided a new series of 2-substituted phenylnitronyl nitroxide derivatives 6a-s. The newly synthesized compounds 6a-s possess improved radical scavenger's activity based on PC12 cell survival assay. Compounds 6g,n,o, and s are some of the most potent compounds in terms of NO, H(2)O(2), and OH scavenging ability. 2-Substitued phenylnitronyl nitroxides had a higher radical scavenging activity with the electron-donating group (EDG). In contrast, the introduction of electron-withdrawing group (EWG) to the aromatic ring led to a dramatic decrease in its radical scavenging activity. These results suggest that the electron-donating group (EDG) of the aromatic ring may be an important factor influencing the radical scavenging behavior of these compounds, and the potency of free radical scavenging activity largely depended on the position and electronic properties of the phenyl ring substituents. The enhanced radical scavenging capacities of the novel 2-substituted nitronyl nitroxides may be potential drug leads against the deleterious action of ROS (reactive oxygen species)/RNS (reactive nitrogen species).     

Novel quinazoline derivatives bearing various 6-benzamide moieties as highly selective and potent EGFR inhibitors

A series of novel quinazoline derivatives bearing various C-6 benzamide substituents were synthesized and evaluated as EGFR inhibitors, and most showed significant inhibitory potency against EGFR kinase. In particular, compound 6g possessed potent inhibitory activity against EGFR wild-type (IC₅₀?=?5?nM), and strong antiproliferative activity against HCC827 and Ba/F3 (L858R) cell lines. Kinase profiling against a panel of 365 kinases showed that 6g was highly selective for EGFR. Furthermore, 6g showed desirable properties in assays of liver microsome metabolic stability and cytochromes P450 inhibition and preliminary pharmacokinetic study. The overall attractive profile of 6g made it an interesting compound for further development.     

Oxoquinoline acyclonucleoside phosphonate analogues as a new class of specific inhibitors of human immunodeficiency virus type 1

The emergence of a multidrug-resistant HIV-1 strain and the toxicity of anti-HIV-1 compounds approved for clinical use are the most significant problems facing antiretroviral therapies. Therefore, it is crucial to find new agents to overcome these issues. In this study, we synthesized a series of new oxoquinoline acyclonucleoside phosphonate analogues (ethyl 1-[(diisopropoxyphosphoryl)methyl]-4-oxo-1,4-dihydroquinoline-3-carboxylates 3a-3k), which contained different substituents at the C6 or C7 positions of the oxoquinoline nucleus and an N1-bonded phosphonate group. We subsequently investigated these compounds' in vitro inhibitory effects against HIV-1-infected peripheral blood mononuclear cells (PBMCs). The most active compounds were the fluoro-substituted derivatives 3f and 3g, which presented excellent EC(50) values of 0.4±0.2 μM (3f) and 0.2±0.005 μM (3g) and selectivity index values (SI) of 6240 and 14675, respectively.     

Synthesis and antiproliferative activity of 2,7-diamino l0-(3,5-dimethoxy)benzyl-9(10H)-acridone derivatives as potent telomeric G-quadruplex DNA ligands

A novel series of l0-(3,5-dimethoxy)benzyl-9(10H)-acridone derivatives with terminal ammonium substituents at C2 and C7 positions on the acridone ring were successfully synthesized as antiproliferation agents. The biologic activity of the acridone compounds against leukemia CCRF-CEM cells demonstrated that some of the compounds displayed good antiproliferative activity, among which compound 6a containing dimethylamine substituents at the terminal C2 and C7 positions exhibited the highest cytotoxicity with IC₅₀ at 0.3 μM. In addition compound 6a showed little toxicity against normal 293T cells proliferation with IC₅₀ more than 100 μM. Further study indicated that compound 6a had strong binding activity to human telomeric G-quadruplex DNA, as detected by mass spectrometry, CD spectroscopy, UV absorption, FRET and fluorescence quenching assays. Our data suggested that the activity of 6a might be associated with its stabilization of G-quadruplex DNA, which can be developed as potent antitumor agent.     

Synthesis and antienteroviral activity of a series of novel, oxime ether-containing pyridyl imidazolidinones

A series of novel, oxime ether-containing pyridyl imidazolidinones were synthesized and their antiviral activity was evaluated in a plaque reduction assay. It is very interesting that this class of compounds is specific for human enteroviruses, in particular, enterovirus 71 (EV71). Some derivatives strongly inhibited enterovirus replication with activities higher or comparable to those of the reference compounds such as A1 and A2. Preliminary SAR studies revealed that the chain length of the alkyl linker and the alkyl substituent at the oxime ether group largely influenced the in vitro anti-EV71 activity of this new class of potent antiviral agents. Among this series of compounds synthesized, the pyridyl imidazolidinone with an ethyl oxime ether group located at the para position of the phenoxyl ring (8b) was identified as the most potent enterovirus 71 inhibitor (IC50=0.001 microM) with no apparent cytotoxic effect toward RD (rhabdomyosarcoma) cell lines (CC50>25 microM). Furthermore, this compound has been shown broad-spectrum activity against most of the serotypes of enteroviruses tested in the nanomolar range.     

Design, synthesis and biological activity of thiazolidine-4-carboxylic acid derivatives as novel influenza neuraminidase inhibitors

A series of thiazolidine-4-carboxylic acid derivatives were synthesized and evaluated for their ability to inhibit neuraminidase (NA) of influenza A virus. All the compounds were synthesized in good yields starting from commercially available l-cysteine hydrochloride using a suitable synthetic strategy. These compounds showed moderate inhibitory activity against influenza A neuraminidase. The most potent compound of this series is compound 4f (IC(50)=0.14 μM), which is about sevenfold less potent than oseltamivir and could be used to design novel influenza NA inhibitors that exhibit increased activity based on thiazolidine ring.     

Synthesis and RET protein kinase inhibitory activity of 3-arylureidobenzylidene-indolin-2-ones

A novel series of 3-arylureidobenzylidene-indolin-2-ones was synthesized and their inhibitory activity against Ret tyrosine kinase investigated in comparison with the Ret inhibitor RPI-1 as a reference compound for this series. A few compounds were able to revert the RETC634R oncogene-transformed morphologic phenotype of NIH3T3(MEN2A) cells and showed a selective antiproliferative activity against these cells as compared to parental NIH3T3 cells or NIH3T3 cells transformed with a non-tyrosine kinase oncogene (NIH3T3(H-RAS)). Inhibition of Ret enzyme activity by effective derivatives was confirmed in a kinase assay. Structure-activity relationship indicated a favourable activity for 5,6-dimethoxyindolinone derivatives with H, OH, or OMe in the para position of the distal aryl ring.     

Synthesis and biological evaluation of novel 4-azaindolyl-indolyl-maleimides as glycogen synthase kinase-3β (GSK-3β) inhibitors

A series of novel 4-azaindolyl-indolyl-maleimides were synthesized and evaluated for their GSK-3β inhibitory activity. Most compounds exhibited high potency to GSK-3β. Among them, compound 7c was the most promising GSK-3β inhibitor. Preliminary structure–activity relationships were discussed based on the experimental data obtained and showed that different substituents on the indole ring and side chains at 1-position of indole had varying degrees of influence on the GSK-3β inhibitory potency. In a cell-based functional assay, compounds 7c and 15a significantly reduced Aβ-induced Tau hyperphosphorylation by inhibiting GSK-3β.     

Synthesis and insecticidal activity of novel N-oxydihydropyrrole derivatives with a substituted spirocyclohexyl group

A series of 5-spirocyclohexyl-3-(2,6-dimethylphenyl)-1,5-dihydro-2H-pyrrol-2-one derivatives (3) with various substituents on the spirocyclohexyl ring was synthesized and evaluated for its insecticidal activity against the aphid, Myzus persicae. Substituents at the 1- and 4-positions of the dihydropyrrole ring were also varied to optimize the activity. An investigation of the structure-activity relationship revealed that methoxy, alkoxyalkoxy, ethylenedioxy and methoxyimino groups were favorable as substituents at the 4-position of the spirocyclohexyl ring. The activity was optimized by the respective substitution of a methoxy or methoxymethoxy moiety and cyclopropylcarbonyloxy group at the 1- and 4-positions of the dihydropyrrole ring.