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Study of the structure-bioactivity of fleximers: synthesis, crystal structure, Hirshfeld surface analysis, and anti-inflammatory assays
Synthesized and natural pyridones/pyridines derivatives exhibiting diverse biological activities. 2-pyridone has lactam-lactim tautomerization like thymine and uracil bases. In this study, COX-2 target based series of pyridone/pyridine linked fleximers were designed, synthesized and studied. All analogues binding affinity with COX-2 active site were studied through molecular docking, and anti-inflammatory activity studied by in vivo analysis. Weak interactions were studied to find binding sites among analogues through crystal packing, Hirshfeld surface analysis and in silico analysis. All the analogues exhibited anti-inflammatory activity, while compound (3) is the most active analogue among the series. In contrast, since compound (3) is a pyridine-phthalimide ring-containing analogue, the presence of a phthalimide group probably favors anti-inflammatory activity over other types of rings. The results suggested further investigations on compounds as anti-inflammatory prodrugs.
Singh, Ved Prakash,Dowarah, Jayanta,Marak, Brilliant N.,Sran, Balkaran Singh,Tewari, Ashish Kumar
(2021/05/05)

Development of Membrane-Active Honokiol/Magnolol Amphiphiles as Potent Antibacterial Agents against Methicillin-Resistant Staphylococcus aureus (MRSA)
Currently, infections caused by drug-resistant bacteria have become a new challenge in anti-infective treatment, seriously endangering public health. In our continuous effort to develop new antimicrobials, a series of novel honokiol/magnolol amphiphiles were prepared by mimicking the chemical structures and antibacterial properties of cationic antimicrobial peptides. Among them, compound 5i showed excellent antibacterial activity against Gram-positive bacteria and clinical MRSA isolates (minimum inhibitory concentrations (MICs) = 0.5-2 μg/mL) with low hemolytic and cytotoxic activities and high membrane selectivity. Moreover, 5i exhibited rapid bactericidal properties, low resistance frequency, and good capabilities of disrupting bacterial biofilms. Mechanism studies revealed that 5i destroyed bacterial cell membranes, resulting in bacterial death. Additionally, 5i displayed high biosafety and potent in vivo anti-infective potency in a murine sepsis model. Our study indicates that these honokiol/magnolol amphiphiles shed light on developing novel antibacterial agents, and 5i is a potential antibacterial candidate for combating MRSA infections.
Bai, Li-Ping,Fu, Xiangjing,Guo, Yong,Han, Meiyue,Hou, Enhua,Liu, Jifeng,Qin, Shangshang,Wen, Tingyu,Yan, Xiaoting
supporting information
p. 12903 - 12916
(2021/09/13)

Preparation method 3 - phenoxybromopropane or analogue thereof
The invention discloses a preparation method of 3 -phenoxybromopropane or an analogue thereof, wherein 3 - phenoxybromopropane and an allyl compound thereof are obtained through substitution reaction and addition reaction so as to avoid the inconvenience of using gaseous hydrogen bromide, 2nd-step addition reaction is realized by using the brominated salt and the acid in situ, and the process is simple in operation. The condition is easy to control, the atom economy is good, the aspect of environmental impact is low pollution, zero emission accords with the current green chemical synthesis direction, and the cost is economic.
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(2021/11/26)

Synthesis of Medium-Ring-Sized Benzolactams by Using Strong Electrophiles and Quantitative Evaluation of Ring-Size Dependency of the Cyclization Reaction Rate
Benzolactams with medium-sized rings were synthesized via the electrophilic aromatic substitution reaction of carbamoyl cations (R1R2N+═C═O) in good to high yields without dilution. These reactions were utilized to quantitatively examine the extent of retardation of medium-sized ring formation, compared to five- or six-membered ring formation. The order of reaction rates of formation of cyclic benzolactams is six- > five- > seven- > eight- > nine-membered ring at 25 °C. The present reaction provides a route to eight- A nd nine-membered benzolactams.
Kurouchi, Hiroaki,Ohwada, Tomohiko
p. 876 - 901
(2019/12/30)

Preparation method of high-purity 3-phenoxypropyl bromide
The invention discloses a preparation method of aclidinium bromide key intermediate 3-phenoxypropyl bromide (formula I). The method comprises the following steps: by taking phenol and halogenated propanol as raw materials, carrying out nucleophilic substitution reaction under an alkaline condition to generate 3-phenoxy propanol, then reacting with a sulfonic acid esterification reagent to generateactive ester of 3-phenoxy propanol, refining the ester, and then reacting with a bromide of an alkali metal to generate 3-phenoxypropyl bromide. The preparation method provided by the invention has the advantages of cheap and easily available raw materials, simple operation, mild reaction conditions, no harsh reaction conditions, and high yield and purity of the obtained product, and is suitablefor industrial production.
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Paragraph 0050-0061; 0065-0067

(2020/05/01)

Indolyl Azaspiroketal Mannich Bases Are Potent Antimycobacterial Agents with Selective Membrane Permeabilizing Effects and in Vivo Activity
The inclusion of an azaspiroketal Mannich base in the membrane targeting antitubercular 6-methoxy-1-n-octyl-1H-indole scaffold resulted in analogs with improved selectivity and submicromolar activity against Mycobacterium tuberculosis H37Rv. The potency enhancing properties of the spiro-fused ring motif was affirmed by SAR and validated in a mouse model of tuberculosis. As expected for membrane inserting agents, the indolyl azaspiroketal Mannich bases perturbed phospholipid vesicles, permeabilized bacterial cells, and induced the mycobacterial cell envelope stress reporter promoter piniBAC. Surprisingly, their membrane disruptive effects did not appear to be associated with bacterial membrane depolarization. This profile was not uniquely associated with azaspiroketal Mannich bases but was characteristic of indolyl Mannich bases as a class. Whereas resistant mycobacteria could not be isolated for a less potent indolyl Mannich base, the more potent azaspiroketal analog displayed low spontaneous resistance mutation frequency of 10-8/CFU. This may indicate involvement of an additional envelope-related target in its mechanism of action.
Nyantakyi, Samuel Agyei,Li, Ming,Gopal, Pooja,Zimmerman, Matthew,Dartois, Véronique,Gengenbacher, Martin,Dick, Thomas,Go, Mei-Lin
supporting information
p. 5733 - 5750
(2018/06/20)

Design, synthesis, and biological evaluation of novel pan agonists of FFA1, PPARγ and PPARδ
The free fatty acid receptor 1 (FFA1) and peroxisome proliferator-activated receptors (PPARs) have attracted interest as potent targets for the treatment of metabolic syndrome such as type 2 diabetes. Based on the hypothesis that the dual agonists of PPARs and FFA1 would act as insulin sensitizers and secretagogues by simultaneous activation of PPARs and FFA1, we developed the design strategy to obtain dual PPARs/FFA1 agonist by hybrid FFA1 agonist 1 with PPARδ agonist 2 in consideration of their structural similarity. As expected, systematic exploration of structure-activity relationship and molecular modeling, results in the discovery of lead compound 15, a pan agonist with relative balanced activities between FFA1, PPARγ and PPARδ. The dose-response relationship studies suggested that the pan agonist 15 suppressed the excursion of blood glucose levels in a dose-dependent manner. During a 5-days treatment in ob/ob mice, the pan agonist 15 (100 mg/kg) revealed sustained hypoglycemic effect, even proximity to the most advanced FFA1 agonist (TAK-875, 40 mg/kg), which might be attributed to its pan PPARs/FFA1 activities to simultaneous regulate the mechanism of insulin secretion and resistance. These positive results suggest that the dual PPARs/FFA1 agonists such as lead compound 15 might be novel therapeutic strategy to modulate the complex pathological mechanisms of type 2 diabetes.
Li, Zheng,Zhou, Zongtao,Deng, Fengjian,Li, Yuyi,Zhang, Danjun,Zhang, Luyong
supporting information
p. 267 - 276
(2018/10/15)

Discovery and structure-activity relationship studies of N-substituted indole derivatives as novel Mcl-1 inhibitors
Myeloid cell leukemia-1 (Mcl-1) is an important antiapoptotic protein functioning through protein-protein interactions. We discovered LSL-A6 (2-((2-carbamoyl-1-(3-(4-methoxyphenoxy)propyl)-1H-indol-6-yl)oxy)acetic acid) with a novel N-substituted indole scaffold to interfere Mcl-1 binding as a novel Mcl-1 inhibitor. Molecular modeling indicated that this compound binds with Mcl-1 by interaction with P2 and R263 hot-spots. Structure modification focused on several moieties including indole core, hydrophobic tail and acidic chain were conducted and structure-activity relationship was analyzed. The most potent compound 24d which exhibited Ki value of 110?nM for interfering Mcl-1 binding was obtained after hit-to-lead modification.
Luan, Shenglin,Ge, Qi,Chen, Yedong,Dai, Mingyang,Yang, Jinyu,Li, Kun,Liu, Dan,Zhao, Linxiang
supporting information
p. 1943 - 1948
(2017/04/07)

Design, Synthesis, and Biological Evaluation of Coupled Bioactive Scaffolds as Potential Anticancer Agents for Dual Targeting of Dihydrofolate Reductase and Thioredoxin Reductase
The dihydrofolate reductase (DHFR) and thioredoxin reductase (TrxR) enzymes are involved in the process of tumor cell growth and survival. The 4,6-diamino-1,2-dihydro-1,3,5-triazine scaffold is well-established as a useful scaffold for DHFR inhibition, while chalcones have been reported to be inhibitors of TrxR. In this study, 15 novel compounds designed by the structural combination of the 4,6-diamino-1,2-dihydro-1,3,5-triazine and chalcone scaffolds via a diether linker were successfully synthesized and characterized. All of the compounds demonstrated dual inhibition against DHFR and TrxR when they were assessed by in vitro enzyme assays. The compounds also exhibited antiproliferative activity against the MCF-7 and HCT116 cells. The more potent analogs 14 and 15 were found to inhibit cellular DHFR and TrxR activities in HCT116 cells. Therefore, this study provided compelling evidence that 14 and 15 could exert their anticancer property via multitarget inhibition at the cellular level.
Ng, Hui-Li,Ma, Xiang,Chew, Eng-Hui,Chui, Wai-Keung
supporting information
p. 1734 - 1745
(2017/03/17)

LSD1 Inhibitors
The present invention relates to compounds that inhibit LSD1 activity. In particular, the present invention relates to compounds, pharmaceutical compositions and methods of use, such as methods of treating cancer using the compounds and pharmaceutical compositions of the present invention.
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Paragraph 0371; 0372

(2017/07/14)

Design, synthesis, docking studies and biological evaluation of novel dihydro-1,3,5-triazines as human DHFR inhibitors
A novel series of dihydro-1,3,5-triazine derivatives bearing a heteroatom spiro-ring were designed and synthesized on the basis of molecular flexible docking work, and their biological activities were evaluated. Compounds A2, A5, B1 and B3 showed potent human dihydrofolate reductase (hDHFR) inhibitory activity with IC50values of 7.46 nM, 3.72 nM, 6.46 nM, 4.08 nM, versus reference drug methotrexate (MTX). From the molecular docking result we concluded that the conformation space generated by deformation of the flexible residue Phe31 is favorable for the binding of the spiro-ring, and inserting heteroatom into spiro ring might increase the binding affinity. There were 24 compounds with broadspectrum antiproliferative activity against several tumor cell lines (HCT116, A549, HL-60, HepG2 and MDA-MB-231) with IC50values ranging from 0.79 to 0.001 μM. The antitumor activity in?vivo of compound A2 was determined in a human alveolar basal epithelial cell line A549 xenograft model. This study offered novel anticancer agents with high inhibitory activity that target hDHFR and have a binding mode of the novel molecular scaffold with hDHFR. This provides potent support for further development of novel hDHFR inhibitors.
Zhou, Xiaotian,Lin, Kuaile,Ma, Xiang,Chui, Wai-Keung,Zhou, Weicheng
p. 1279 - 1288
(2016/11/29)

Substrate-Dependent Cleavage Site Selection by Unconventional Radical S-Adenosylmethionine Enzymes in Diphthamide Biosynthesis
S-Adenosylmethionine (SAM) has a sulfonium ion with three distinct C-S bonds. Conventional radical SAM enzymes use a [4Fe-4S] cluster to cleave homolytically the C5′,adenosine-S bond of SAM to generate a 5′-deoxyadenosyl radical, which catalyzes various downstream chemical reactions. Radical SAM enzymes involved in diphthamide biosynthesis, such as Pyrococcus horikoshii Dph2 (PhDph2) and yeast Dph1-Dph2 instead cleave the Cγ,Met-S bond of methionine to generate a 3-amino-3-carboxylpropyl radical. We here show radical SAM enzymes can be tuned to cleave the third C-S bond to the sulfonium sulfur by changing the structure of SAM. With a decarboxyl SAM analogue (dc-SAM), PhDph2 cleaves the Cmethyl-S bond, forming 5′-deoxy-5′-(3-aminopropylthio) adenosine (dAPTA, 1). The methyl cleavage activity, like the cleavage of the other two C-S bonds, is dependent on the presence of a [4Fe-4S]+ cluster. Electron-nuclear double resonance and mass spectroscopy data suggests that mechanistically one of the S atoms in the [4Fe-4S] cluster captures the methyl group from dc-SAM, forming a distinct EPR-active intermediate, which can transfer the methyl group to nucleophiles such as dithiothreitol. This reveals the [4Fe-4S] cluster in a radical SAM enzyme can be tuned to cleave any one of the three bonds to the sulfonium sulfur of SAM or analogues, and is the first demonstration a radical SAM enzyme could switch from an Fe-based one electron transfer reaction to a S-based two electron transfer reaction in a substrate-dependent manner. This study provides an illustration of the versatile reactivity of Fe-S clusters.
Dong, Min,Horitani, Masaki,Dzikovski, Boris,Freed, Jack H.,Ealick, Steven E.,Hoffman, Brian M.,Lin, Hening
supporting information
p. 5680 - 5683
(2017/05/04)

Curcumin derivative and preparation method and application thereof
The invention relates to the field of medicinal chemistry and discloses a synthesis method of a curcumin derivative (I) and application thereof to preparation of a near-infrared small-molecule probe used for early diagnosis of the Alzheimer's disease. Experiments prove that the related compound has good selectivity on soluble Abeta, fluorescence intensity is obviously enhanced after the compound is combined with the soluble Abeta, and the most potential near-infrared fluorescent small-molecule probe with soluble Abeta selectivity has the selectivity on soluble Abeta. The molecular formula is described in the description.
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Paragraph 0036; 0037; 0038; 0040; 0041; 0042; 0043

(2016/10/09)

DOPAMINE D2 RECEPTOR LIGANDS
The present invention relates to novel dopamine D2 receptor ligands. The invention further relates to functionally-biased dopamine D2 receptor ligands and the use of these compounds for treating or preventing central nervous system and systemic disorders associated with dysregulation of dopaminergic activity. The present invention relates to novel compounds that modulate dopamine D2 receptors. In particular, compounds of the present invention show functional selectivity at the dopamine D2 receptors and exhibit selectivity downstream of the D2 receptors, on the 0- arrestin pathway and/or on the cAMP pathway.
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Page/Page column 126

(2016/07/05)

DOPAMINE D2 RECEPTOR LIGANDS
The present invention relates to novel dopamine D2 receptor ligands. The invention further relates to functionally-biased dopamine D2 receptor ligands and the use of these compounds for treating or preventing central nervous system and systemic disorders associated with dysregulation of dopaminergic activity.
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Page/Page column 118; 119; 125

(2016/07/05)

Diamino triazines derivatives, their salts, preparation method, composition and use thereof
The invention discloses derivatives and salts of damino dihydrotriazine, and a preparation method, a composition and application thereof. According to the invention, the preparation method of the damino dihydrotriazine derivative and the damino dihydrotriazine salt can be realized by adopting a method I or a method II, wherein the method I includes the step of obtaining a general formula I compound prepared through the reaction between a general formula IV compound and a general formula V compound, while the method II includes the step of mixing a general formula VIII compound with a general formula II compound under an acidic condition, and obtaining the compound shown in the general formula I through a cyclization reaction of the mixture. The invention also provides application of derivatives and salts of the damino dihydrotriazine in preparation of human dihydrofolate reductase inhibitors, preventing and curing drugs for tumor or bacterial infection diseases. The invention further provides a drug composition, which comprises an effective amount of the derivatives and/or salts of the damino dihydrotriazine, as well as pharmaceutically acceptable carriers. According to the invention, spiro heterocyclic ring derivatives of the damino dihydrotriazine have an excellent inhibitory activity on human dihydrofolate reductase, tumor cells and bacteria.
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Page/Page column 0174; 0175; 0176

(2016/10/07)

Efficacy of novel phenoxyalkyl pyridinium oximes as brain-penetrating reactivators of cholinesterase inhibited by surrogates of sarin and VX
Pyridinium oximes are strong nucleophiles and many are effective reactivators of organophosphate-inhibited cholinesterase (ChE). However, the current oxime reactivators are ineffective at crossing the blood-brain barrier and reactivating brain ChE in the intact organism. Our laboratories have developed a series of substituted phenoxyalkyl pyridinium oximes (US patent 9,227,937 B2) with the goal of identifying reactivators effective in crossing the blood-brain barrier. The first 35 of the series were found to have similar in?vitro efficacy as reactivators of ChE inhibited by a sarin surrogate (phthalimidyl isopropyl methylphosphonate, PIMP) or a VX surrogate (nitrophenyl ethyl methylphosphonate, NEMP) in bovine brain preparations as previously observed in rat brain preparations. A number of these novel oximes have shown the ability to decrease the level of ChE inhibition in the brains of rats treated with a high sublethal dosage of either a sarin surrogate (nitrophenyl isopropyl methylphosphonate, NIMP) or the VX surrogate NEMP. Levels of reactivation at 2?h after oxime administration were up to 35% while the currently approved therapeutic, 2-PAM, yielded no reduction in brain ChE inhibition. In addition, there was evidence of attenuation of seizure-like behavior with several of the more effective novel oximes, but not 2-PAM. Therefore these novel oximes have demonstrated an ability to reactivate inhibited ChE in brain preparations from two species and in?vivo data support their ability to enter the brain and provide a therapeutic action. These novel oximes have the potential to be developed into improved antidotes for nerve agent therapy.
Chambers, Janice E.,Chambers, Howard W.,Funck, Kristen E.,Meek, Edward C.,Pringle, Ronald B.,Ross, Matthew K.
p. 154 - 159
(2016/12/06)

Catalytic Access to Alkyl Bromides, Chlorides and Iodides via Visible Light-Promoted Decarboxylative Halogenation
Herein is reported the catalytic, visible light-promoted, decarboxylative halogenation (bromination, chlorination, and iodination) of aliphatic carboxylic acids. This operationally-simple reaction tolerates a range of functional groups, proceeds at room temperature, and is redox neutral. By employing an iridium photocatalyst in concert with a halogen atom source, the use of stoichiometric metals such as silver, mercury, thallium, and lead can be circumvented. This reaction grants access to valuable synthetic building blocks from the large pool of cheap, readily available carboxylic acids.
Candish, Lisa,Standley, Eric A.,Gómez-Suárez, Adrián,Mukherjee, Satobhisha,Glorius, Frank
p. 9971 - 9974
(2016/07/19)

Scalable anti-Markovnikov hydrobromination of aliphatic and aromatic olefins
To improve access to a key synthetic intermediate we targeted a direct hydrobromination-Negishi route. Unsurprisingly, the anti-Markovnikov addition of HBr to estragole in the presence of AIBN proved successful. However, even in the absence of an added initiator, anti-Markovnikov addition was observed. Re-examination of early reports revealed that selective Markovnikov addition, often simply termed "normal" addition, is not always observed with HBr unless air is excluded, leading to the rediscovery of a reproducible and scalable initiator-free protocol.
Galli, Marzia,Fletcher, Catherine J.,Del Pozo, Marc,Goldup, Stephen M.
supporting information
p. 5622 - 5626
(2016/07/06)

ω-Phenoxyalkyl substituted bis(indenyl)zirconium dichloride complexes as catalysts for homogeneous ethylene polymerization
Nine bis(indenyl)zirconium dichloride complexes of the type [C9H6-(CH2)n-O-Ar]2ZrCl2 (n = 3-5; Ar = Ph, t-Bu-Ph) were synthesized, characterized, activated with methylalumoxane (MAO) and tested for ethylene polymerization. Structure-property-relationship studies showed that the activities of the catalysts depend on the length of the bridging chain between the indenyl and the phenoxy group as well as on the bulk at the phenoxy substituent. A t-Bu substituent at the ortho position of the phenoxy group (5a/MAO) gives a much higher catalyst activity (27,500 kg PE/mol cat h) than the isomer 8a/MAO with a t-Bu substituent at the para position of the phenoxy group (16,700 kg PE/mol cat h). Obviously substituents in the ortho position of the phenyl ring generate a bulkier catalyst cation and this can keep the MAO anion at a further distance to allow easier ethylene coordination and chain growth in the polymerization steps. The mono substituted bis(indenyl) complex (C9H7)[C9H6-(CH2)4-O-4-t-Bu]ZrCl2 shows lower activity (11,700 kg PE/mol cat h) than 8a indicating that the electronic effect is dominating in this type of catalysts.
Ahmad, Khalil,Alt, Helmut G.
p. 63 - 71
(2015/06/02)

SMALL MOLECULE INHIBITORS OF MCL-1 AND USES THEREOF
This invention is in the field of medicinal chemistry. In particular, the invention relates to a new class of small-molecules having pyrazolopyridine structure which function as inhibitors of Mcl-1 protein, and their use as therapeutics for the treatment of cancer and other diseases.
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Paragraph 0149

(2015/10/28)

Novel Carboline Derivatives as Potent Antifungal Lead Compounds: Design, Synthesis, and Biological Evaluation
A series of novel antifungal carboline derivatives was designed and synthesized, which showed broad-spectrum antifungal activity. Particularly, compound C38 showed comparable in vitro antifungal activity to fluconazole without toxicity to human embryonic lung cells. It also exhibited good fungicidal activity against both fluconazole-sensitive and -resistant Candida albicans cells and had potent inhibition activity against Candida albicans biofilm formation and hyphal growth. Moreover, C38 showed good synergistic antifungal activity in combination with fluconazole (FLC) against FLC-resistant Candida species. Preliminary mechanism studies revealed that C38 might act by inhibiting the synthesis of fungal cell wall.
Wang, Shengzheng,Wang, Yan,Liu, Wei,Liu, Na,Zhang, Yongqiang,Dong, Guoqiang,Liu, Yang,Li, Zhengang,He, Xiaomeng,Miao, Zhenyuan,Yao, Jianzhong,Li, Jian,Zhang, Wannian,Sheng, Chunquan
p. 506 - 511
(2014/06/09)

Room temperature, metal-free arylation of aliphatic alcohols
Diaryliodonium salts are demonstrated as efficient arylating agents of aliphatic alcohols under metal-free conditions. The reaction proceeds at room temperature within 90 min to give alkyl aryl ethers in good to excellent yields. Aryl groups with electron
Ghosh, Raju,Lindstedt, Erik,Jalalian, Nazli,Olofsson, Berit
p. 54 - 57
(2014/05/06)

SINGLET OXYGEN-LABILE LINKERS AND METHODS OF PRODUCTION AND USE THEREOF
Activatable compositions that include at least one functional moiety and at least one cleavable linker directly or indirectly linked to the at least one functional moiety are disclosed. The at least one functional moiety is inactive when linked to the linker and activated upon cleavage of the linker. Methods of production and use of the activatable composition are also disclosed.
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Paragraph 000181

(2013/11/18)

NOVEL ANTIMICROBIAL COMPOUNDS
A new class of biotin protein ligase (BPL) inhibitors that have antibacterial activity against multiple Staphylococcus aureus isolates, including clinically important methicillin-resistant S. aureus (MRSA) are disclosed that are non-toxic.
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Page/Page column 17

(2013/04/10)

Evaluation of novel aryloxyalkyl derivatives of imidazole and 1,2,4-triazole as heme oxygenase-1 (HO-1) inhibitors and their antitumor properties
A novel series of aryloxyalkyl derivatives of imidazole and 1,2,4-triazole, 17-31, was designed and synthesized as inhibitors of heme oxygenase-1 (HO-1) and heme oxygenase-2 (HO-2). Some of these compounds were found to be good inhibitors of HO-1, in particular those carrying an imidazole moiety as azolyl group and a 3-bromo or 4-iodophenyl as aryl moiety. The most potent compounds 6 and 30 were selected and studied for their antitumor properties in a model of LAMA-84 R cell line overexpressing HO-1 and resistant to imatinib mesylate (IM), a tyrosine-kinase inhibitor used in the treatment of multiple types of cancer, most notably Philadelphia Chromosome positive (Ph+) Chronic Myelogenous Leukemia (CML). Results show that both 6 and 30 sensitized LAMA-84 R cell line to antitumor properties of IM.
Salerno, Loredana,Pittalà, Valeria,Romeo, Giuseppe,Modica, Maria N.,Siracusa, Maria A.,Di Giacomo, Claudia,Acquaviva, Rosaria,Barbagallo, Ignazio,Tibullo, Daniele,Sorrenti, Valeria
p. 5145 - 5153
(2013/09/02)

Click and photo-unclick chemistry of aminoacrylate for visible light-triggered drug release
"Click and Photo-unclick Chemistry" of aminoacrylates is proposed for a new photo-labile linker. Adducts are built in 2 steps with good yields and cleaved rapidly by tissue penetrable visible light (690 nm) with a photosensitizer. Facile synthesis, release of mother drug, and stability and cleavage in medium are demonstrated.
Bio, Moses,Nkepang, Gregory,You, Youngjae
supporting information; experimental part
p. 6517 - 6519
(2012/07/28)

Design, synthesis and structure-activity relationships of new triazole derivatives containing N-substituted phenoxypropylamino side chains
The incidence of invasive fungal infections and resistance to antifungal agents is increasing dramatically. It is highly desirable to develop novel azoles with improved biological profiles. The structure-activity relationship (SAR) of the N-substitutions was investigated in this study. In vitro antifungal activities revealed that sterically large groups were not favored for the N-substitutions. The removal of the N-substitutions had little effect on the antifungal activity. Two compounds with free amine group (i.e. 9a and 10a) showed excellent activity with broad antifungal spectrum. The SAR results were supported by molecular docking and the N-substitutions were found to be important for the conformation of the side chains. The SAR and binding mode of the azoles are useful for further lead optimization.
Wang, Shengzheng,Jin, Gang,Wang, Wenya,Zhu, Lingjian,Zhang, Yongqiang,Dong, Guoqiang,Liu, Yang,Zhuang, Chunlin,Miao, Zhenyuan,Yao, Jianzhong,Zhang, Wannian,Sheng, Chunquan
experimental part
p. 292 - 299
(2012/08/07)

Synthesis, biological evaluation, and molecular modeling of berberine derivatives as potent acetylcholinesterase inhibitors
By targeting the dual active sites of acetylcholinesterase (AChE), a new series of berberine derivatives was designed, synthesized, and evaluated as AChE inhibitors. Most of the derivatives inhibited AChE in the sub-micromolar range. Compound 8c, berberine linked with phenol by a 4-carbon spacer, showed the most potent inhibition of AChE. A kinetic study of AChE and BuChE indicated that a mix-competitive binding mode existed for these berberine derivatives. Molecular modeling studies confirmed that these hybrids target both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. This is the first report where AChE inhibitory activity has been associated with berberine as a lead molecule.
Huang, Ling,Shi, Anding,He, Feng,Li, Xingshu
experimental part
p. 1244 - 1251
(2010/05/02)

The photocatalytic activity of novel, substituted porphyrin/TiO2-based composites
Four novel porphyrins, 5-[3-(3-phenoxy)-propoxy]phenyl porphyrin, 5,15-di-[3-(3-phenoxy)-propoxy]phenyl porphyrin, 5,10,15-tri-[3-(3-phenoxy)-propoxy]phenyl porphyrin, 5,10,15,20-tetra-[3-(3-phenoxy)-propoxy]phenyl porphyrin, and their corresponding Cu(II) porphyrins, were synthesized and characterized spectroscopically. The photodegradation of 4-nitrophenol in aq. suspension was used to determine the photocatalytic activity of polycrystalline TiO2 samples which had been impregnated with the Cu(II) porphyrins, as sensitizers. The photocatalytic activity of the composite depends mainly on the amount of sensitizer on the TiO2 surface rather than the nature of the substituted porphyrins.
Wang, Chen,Li, Jun,Mele, Giuseppe,Duan, Ming-yue,Lü, Xiang-fei,Palmisano, Leonardo,Vasapollo, Giuseppe,Zhang, Feng-xing
experimental part
p. 183 - 189
(2010/11/16)

NOVEL SEMI-SYNTHETIC GLYCOPEPTIDES AS ANTIBACTERIAL AGENTS
Semi-synthetic glycopeptides having antibacterial activity are described, in particular, the semi-synthetic glycopeptides described herein are made by chemical modification of the a glycopeptide (Compound A, Compound B, Compound H or Compound C) or the monosaccharide made by hydrolyzing the disaccharide moiety of the amino acid-4 of the parent glycopeptide in acidic medium to give the amino acid-4 monosaccharide; conversion of the monosaccharide to the amino-sugar derivative; acylation of the amino substituent on the amino acid-4 amino-substituted sugar moiety on these scaffolds with certain acyl groups; conversion of the amide group in amino acid-3 on these scaffolds to various acylamide, acylsulfonamide, acylsulfonylurea derivatives; aminomethylation with substituent containing sulfonamide or acylsulfonamide group on amino acid-7 through Mannich reaction; and conversion of the acid moiety on the macrocyclic ring of these scaffolds to certain substituted amides. Also provided are methods for the synthesis of the compounds, pharmaceutical compositions containing the compounds, and methods of use of the compounds for the treatment and/or prophylaxis of diseases, especially bacterial infections.
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(2015/03/06)

New azoles with potent antifungal activity: Design, synthesis and molecular docking
In response to the urgent need for novel antifungal agents with improved activity and broader spectrum, computer modeling was used to rational design novel antifungal azoles. On the basis of the active site of lanosterol 14α-demethylase from Candida albicans (CACYP51), a series of new azoles with substituted-phenoxypropyl piperazine side chains were rational designed and synthesized. In vitro antifungal activity assay indicates that the new azoles show good activity against most of the tested pathogenic fungi. Interestingly, the designed compounds are also active against an azole-resistant clinical strain. Compared to fluconazole and itraconazole, several compounds (such as 12i, 12j and 12n) show higher antifungal activity and broader spectrum, which are promising leads for the development of novel antifungal agents.
Che, Xiaoying,Sheng, Chunquan,Wang, Wenya,Cao, Yongbing,Xu, Yulan,Ji, Haitao,Dong, Guoqiang,Miao, Zhenyuan,Yao, Jianzhong,Zhang, Wannian
scheme or table
p. 4218 - 4226
(2009/12/09)

Design, synthesis, and antifungal activity of novel conformationally restricted triazole derivatives
A series of new triazole derivatives were designed and synthesized on the basis of the active site of lanosterol 14α-demethylase from Candida albicans (CACYP51). 2-(2,4-Difluorophenyl)-3-(methyl-(3-phenoxyalkyl)amino)-1- (1H-1,2,4-triazol-1-yl)propan-2-ols show excellent in-vitro activity against most of the tested pathogenic fungi. The MIC80 value of compound 8a against Candida albicans is 0.01 μM, which provides a good starting template for further structural optimization. The binding modes of the designed compounds were investigated by flexible molecular docking. The compounds interacted with CACYP51 through hydrophobic, van-der-Waals, and hydrogenbonding interactions.
Wang, Wenya,Sheng, Chunquan,Che, Xiaoying,Ji, Haitao,Miao, Zhenyuan,Yao, Jianzhong,Zhang, Wannian
experimental part
p. 732 - 739
(2010/06/11)

One-carbon extrusion from a tetraazafulvalene. Isolation of aldehydes and a study of their origin
Reaction of imidazolylidene-derived enetetramine 2 with aliphatic iodides and bromides (and with aryl iodides bearing alkene-containing side-chains in the ortho-position) leads to formation of aliphatic aldehydes through an unprecedented extrusion of a one-carbon unit from the enetetramine. An intermediate 2-alkylimidazoline 24 is proposed, where the alkyl group derives from the substrate; this imidazoline undergoes further reaction in situ to afford the observed aldehydes on acidic workup. Modifiedsubstrates were designed and prepared to probe the chemistry of the alk ylimidazoline adducts and provided extensive information on the chemistry of the adducts.
Murphy, John A.,Schoenebeck, Franziska,Findlay, Neil J.,Thomson, Douglas W.,Zhou, Sheng-ze,Garnier, Jean
supporting information; experimental part
p. 6475 - 6479
(2009/09/26)

Copper(II)-catalyzed ether synthesis from aliphatic alcohols and potassium organotrifluoroborate salts
(Matrix presented) A protocol for the copper(II)-catalyzed etherification of aliphatic alcohols under mild and essentially neutral conditions is described. Air- and moisture-stable potassium alkenyl- and aryltrifluoroborate salts undergo cross-coupling with a variety of aliphatic primary and secondary alcohols and phenols, and are tolerant of a range of functional groups. The optimized conditions utilize catalytic copper(II) acetate with 4-(dimethylamino)pyridine as ligand in the presence of 4 A molecular sieves under an atmosphere of oxygen.
Quach, Tan D.,Batey, Robert A.
p. 1381 - 1384
(2007/10/03)

(±)-2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinolines as a new class of specific bradycardic agents
A series of (±)-2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinolines were prepared and their bradycardic activities were examined in isolated guinea-pigs' right atria and in anesthetized rats. Modifications on the benzyl moiety of the parent compound, 1, led to the identification of compound 11e as a potent and specific bradycardic agent.
Kubota, Hideki,Kakefuda, Akio,Watanabe, Toshihiro,Taguchi, Yasuko,Ishii, Noe,Masuda, Noriyuki,Sakamoto, Shuichi,Tsukamoto, Shin-Ichi
p. 2155 - 2158
(2007/10/03)

Synthesis and Pharmacological Evaluation of 1-Oxo-2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinolines and Related Analogues as a New Class of Specific Bradycardic Agents Possessing If Channel Inhibitory Activity
A series of 1-oxo-2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinolines and related analogues were prepared and evaluated for their bradycardic activities in isolated right atrium and in anesthetized rats. (± )-6,7-Dimethoxy-2-{1- [3-(3,4-methylenedioxyphenoxy)propyl]-3-piperidyl}-1,2,3, 4-tetrahydroisoquinoline (4) was chosen as a lead, and structural modifications were performed on the tetrahydroisoquinoline ring and the terminal aromatic ring. The modifications on the tetrahydroisoquinoline ring revealed that the 1-oxo-1,2,3,4-tetrahydroisoquinoline ring system was optimum structure for both in vitro potency and in vivo efficacy. Furthermore, methoxy, ethoxy, and methoxycarbonyl groups were identified as preferable substituents on the terminal aromatic ring. One of the 1-oxo-1,2,3,4-tetrahydroisoquinoline derivatives, (R)-10a, was further evaluated for its bradycardic activity and inhibitory activity against If currents. Compound (R)-10a demonstrated potent bradycardic activity in rats with minimal influence on blood pressure after oral administration. The compound also showed inhibition of If currents (IC50 = 0.32 μM) in guinea pig pacemaker cells.
Kubota, Hideki,Kakefuda, Akio,Watanabe, Toshihiro,Ishii, Noe,Wada, Koichi,Masuda, Noriyuki,Sakamoto, Shuichi,Tsukamoto, Shin-ichi
p. 4728 - 4740
(2007/10/03)

9-(2-Aryloxyethyl) derivatives of adenine - A new class of non-nucleosidic antiviral agents
New 9-(aryloxyalkyl) derivatives of adenine have been prepared by alkylation of adenine with tosylates, bromides, and α-chloro ethers containing terminal aromatic fragments in anhydrous DMF in the presence of potassium carbonate. The compounds of the 9-(2-phenoxyethyl)adenine series appear to be highly reactive against cytomegaloviruses of mankind in vitro, while derivatives of 9-(2-benzyloxyethyl)adenine demonstrate anti-HIV-1 activity. Compounds with shorter or longer chains, and also compounds which do not have aromatic fragments at the ends of the chains, do not possess antiviral activity.
Petrov,Ozerov,Novikov,Pannecouque,Balzarini,De Clercq
p. 1218 - 1226
(2007/10/03)

Wittig-type olefination catalyzed by PEG-telluride
Soluble poly(ethylene glycol) (PEG)-supported telluride 2 was designed and synthesized for catalytic Wittig-type reactions. It was found that the catalytic loading could be reduced from 20 to 2 mol % by the introduction of PEG (even to 0.5 mol % when some telluride salts were used as the catalyst). Under the catalytic reaction conditions, a wide variety of aldehydes with different structures could react with bromoacetate to afford β-substituted or α,β-disubstituted unsaturated esters in high yields with excellent E-stereoselectivity. The modified process, by using sodium bisulfite instead of triphenyl phosphite, represented a very simple product isolation procedure. The roles of PEG for promoting the ylide formation and stabilizing the catalytic species were disclosed. The mechanism was also studied.
Huang, Zheng-Zheng,Ye, Song,Xia, Wei,Yu, Yi-Hua,Tang, Yong
p. 3096 - 3103
(2007/10/03)

Phenoxypropoxybiguanides, prodrugs of DHFR-inhibiting diaminotriazine antimalarials
A total of 34 analogues of the biguanide PS-15 (5s), a prodrug of the diaminotriazine WR-99210 (8s), have been prepared. Several of them, such as 5b (PS-33) and 5m (PS-26), maintain or exceed the in vivo activity of PS-15 while not requiring the use of highly regulated starting materials. The putative diaminotriazine metabolites of these new analogues (compounds 8) have also been prepared and shown to maintain the activity against resistant P. falciparum strains. The structure-activity relationships of biguanides 5 and putative metabolites 8 are discussed.
Jensen,Ager,Bliss,Canfield,Kotecka,Rieckmann,Terpinski,Jacobus
p. 3925 - 3931
(2007/10/03)

1-[(Aryloxy)alkyl]-1H-imidazoles as inhibitors of neuronal nitric oxide synthase
A series of 1-[(aryloxy)alkyl]-1 H-imidazoles were synthesized from imidazole and various (aryloxy)alkyl bromides and tested for inhibitory activity against the three isoforms of nitric oxide synthase. 1-[2-(4-Bromophenoxy)ethyl]-1 H-imidazole and 1-[2-[4-(trifluoromethyl)phenoxy]ethyl]-1H-imidazole showed inhibitory activity against the neuronal isoform but were less potent against the endothelial isoform. Thus they could be considered interesting for their selectivity. The remaining compounds had only modest activity.
Salerno,Sorrenti,Guerrera,Sarva,Siracusa,Di Giacomo,Vanella
p. 491 - 494
(2007/10/03)

Dendrimeric catalysts for the activation of hydrogen peroxide. Increasing activity per catalytic phenylseleno group in successive generations
(matrix presented) Dendrimeric polyphenylselenides are prepared in high yield using propyloxy spacers to connect the phenyseleno groups to the dendrimeric core. The selenides catalyze the oxidation of bromide with hydrogen peroxide to give positive bromine species that can be captured by cyclohexene in two-phase systems. The increase in the rate of catalysis exceeds statistical contributions for the first few generations with 3, 6, and 12 phenylseleno groups.
Francavilla, Charles,Bright, Frank V.,Detty, Michael R.
p. 1043 - 1046
(2008/02/09)

Octakationische Cyclophane: Bindung von ATP und anderen anionischen Gastmolekuelen in Wasser
Keywords: ATP; Cyclophane; Makrocyclen; Supramolekulare Chemie
Menger, Fredric M.,Catlin, Kelly K.
p. 2330 - 2333
(2007/10/03)

Radical isomerization via intramolecular ipso substitution of aryl ethers: Aryl translocation from oxygen to carbon
Bromopropyl aryl ethers an converted to 3-arylpropanols under standard radical generating conditions in the presence of tributylstannane and AIBN. This rearrangement involves intramolecular ipso attack of the alkyl radicals which generates spiro cyclohexadienyl radical intermediates.
Lee, Eun,Lee, Chulbom,Tae, Jin Sung,Whang, Ho Sung,Li, Kap Sok
p. 2343 - 2346
(2007/10/02)

Selectivity in alkylation of phenols with 1-bromo-3-chloropropane using phase-transfer catalysis
The use of various phase-transfer catalysts in the alkylation of phenol and substituted phenols with 1-bromo-3-chloropropane was investigated. When a quarternary ammonium salt of the general formula R'4N+ X-, where R' = alkyl with a minimum chain length of 4 was used, a mixture of 1-aryloxy-3-chloropropane and 1-aryloxy-3-bromopropane resulted. The effect of counterion, added potassium bromide, and catalysts other than quarternary ammonium salts were assessed for the halopropylation of 2,5-dimethylphenol.
Reinholz,Becker,Hagenbruch,Schafer,Schmitt
p. 1069 - 1071
(2007/10/02)

Synthesis and Hypolipidemic Activity of 2-Substituted Isobutyric Acid Derivatives
A series of 2-substituted isobutyric acid derivatives have been synthesized and evaluated as hypolipidemic agents.Compounds 11 and 20 were found to decrease the level of plasma total cholesterol in experimental hyperlipidemic rats to a greater extent than clofibrate (CF) and to increase the level of plasma high-density lipoprotein cholesterol to the same extent as gemfibrozil (GF).Increase in liver weight caused by these compounds were less than those with CF and GF.
Morishita, Shin-ichi,Saito, Takashi,Hirai, Yasuharu,Shoji, Masamichi,Mishima, Yasuhiro,Kawakami, Masato
p. 1205 - 1209
(2007/10/02)

The mechanism of the photo-induced homolysis of aryl halides
Irradiation of the ω-(4-halophenoxy)alkyl bromides (Ia,b n=10) in methanol usually leads to preferential cleavage of the aryl-halogen bond and data is presented supporting the conclusion that this occurs from the first excited single state.
Davidson, R.Stephen,Goodin, Jonathan W.,Kemp, Graham
p. 2911 - 2914
(2007/10/02)

Ditertiary diamine compounds
The preparation of ditertiary aliphatic diamines 3 designed as drugs protecting CNS acetylcholinesterase against organophosphate inhibition, is described. Owing to the radicals at the basic nitrogen atoms, these compounds should exist in appreciable amounts both as base and as diammonium ion at biological pH's.
Schnekenburger
p. 1853 - 1858
(2007/10/05)