- Synthesis, antimicrobial evaluation, and in silico studies of quinoline—1H-1,2,3-triazole molecular hybrids
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Abstract: Antimicrobial resistance has become a significant threat to global public health, thus precipitating an exigent need for new drugs with improved therapeutic efficacy. In this regard, molecular hybridization is deemed as a viable strategy to afford multi-target-based drug candidates. Herein, we report a library of quinoline—1H-1,2,3-triazole molecular hybrids synthesized via copper(I)-catalyzed azide-alkyne [3 + 2] dipolar cycloaddition reaction (CuAAC). Antimicrobial evaluation identified compound 16 as the most active hybrid in the library with a broad-spectrum antibacterial activity at an MIC80 value of 75.39?μM against methicillin-resistant S. aureus, E. coli, A. baumannii, and multidrug-resistant K. pneumoniae. The compound also showed interesting antifungal profile against C. albicans and C. neoformans at an MIC80 value of 37.69 and 2.36?μM, respectively, superior to fluconazole. In vitro toxicity profiling revealed non-hemolytic activity against human red blood cells (hRBC) but partial cytotoxicity to human embryonic kidney cells (HEK293). Additionally, in silico studies predicted excellent drug-like properties and the importance of triazole ring in stabilizing the complexation with target proteins. Overall, these results present compound 16 as a promising scaffold on which other molecules can be modeled to deliver new antimicrobial agents with improved potency. Graphic abstract: [Figure not available: see fulltext.].
- Awolade, Paul,Cele, Nosipho,Kerru, Nagaraju,Singh, Parvesh
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p. 2201 - 2218
(2020/06/17)
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- Discovery and structure-activity relationship studies of N-substituted indole derivatives as novel Mcl-1 inhibitors
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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
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supporting information
p. 1943 - 1948
(2017/04/07)
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- Discovery of 1-aryloxyethyl piperazine derivatives as Kv1.5 potassium channel inhibitors (part I)
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Kv1.5 potassium channel is an efficacious and safe therapeutic target for the treatment of atrial fibrillation (AF), the most common arrhythmia that threatens human. Herein, by modifying the hit compound 7k from an in-house database, 48 derivatives were synthesized for the assay of their Kv1.5 inhibitory effects by whole cell patch clamp technique. Six compounds which showed better potency than the positive compound dronedarone were selected for the next evaluation of their drug-like properties. Compound 8 exhibited balanced solubility and permeability. It also showed acceptable pharmacodynamics profile with very low acute toxicity. Taking all these data into account, compound 8 can serve as a promising lead for the development of novel therapeutic agent for the treatment of AF.
- Guo, Xiaoke,Ma, Xianglei,Yang, Qian,Xu, Jing,Huang, Lu,Jia, Jianmin,Shan, Jiaojiao,Liu, Li,Chen, Weilin,Chu, Hongxi,Wei, Jinlian,Zhang, Xiaojin,Sun, Haopeng,Tang, Yiqun,You, Qidong
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supporting information
p. 89 - 94
(2014/06/09)
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- Diether derivatives of homo- or substituted piperidines as non-imidazole histamine H3 receptor ligands
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Synthesis and biological activities of a series of homo- or substituted piperidine unsymmetrical diethers are described. The novel compounds were evaluated for histamine H3 receptor binding affinities at recombinant human H3 receptor
- Lazewska, Dorota,Kuder, Kamil,Ligneau, Xavier,Camelin, Jean-Claude,Schunack, Walter,Stark, Holger,Kiec-Kononowicz, Katarzyna
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experimental part
p. 3037 - 3042
(2009/09/30)
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- Synthesis and anticonvulsant evaluation of some N-substituted phthalimides
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Two series of phthalimides - one possessing an N-phenoxyalkyl moiety substituted at position 3 or 4 of the phenyl ring (1-9) and the other of N-alkenyl or alkinyl phthalimides (10-18) - were synthesized, evaluated for anticonvulsant activity and had their in silico lipophilicity estimated using computer programs. The anticonvulsant activity of phthalimides containing an unsaturated substituent at the phthalimide nitrogen was superior to that of the N-phenoxyalkyl phthalimides. Alkinyl derivative 10 emerged as the most active (in MES and ScMet tests) of all the compounds tested. A correlation between anticonvulsant activity and in silico estimated lipophilicity was not observed.
- Wiecek, Malgorzata,Kiec-Kononowicz, Katarzyna
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experimental part
p. 249 - 257
(2009/12/24)
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- CARBOXYLIC ACID DERIVATIVE AND SALT THEREOF
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The present invention provides a novel carboxylic acid compound, a salt thereof or a hydrate of them useful as an insulin sensitizer, and a medicament comprising the compound as an active ingredient. That is, the present invention provides a carboxylic acid compound represented by the following formula, a salt thereof, an ester thereof or a hydrate of them. Wherein R1 represents a hydrogen atom, hydroxyl group, halogen, carboxyl group, or a C1-6 alkyl group etc., each of which may have one or more substituents; L represents a single bond, or a C1-6 alkylene group, a C2-6 alkenylene group or a C2-6 alkynylene group, each of which may have one or more substituents; M represents a single bond, or a C1-6 alkylene group, a C2-6 alkenylene group or a C2-6 alkynylene group, each of which may have one or more substituents; T represents a single bond, or a C1-3 alkylene group, a C2-3 alkenylene group or a C2-3 alkynylene group, each of which may have one or more substituents; W represents a carboxyl group;- - - represents a single bond etc. ; X represents a single bond, oxygen atom, a group represented by -NRX1CQ1O- (wherein Q1 represents an oxygen atom or sulfur atom; and RX1 represents a hydrogen atom, formyl group, or a C1-6 alkyl group etc., each of which may have one or more substituents), -OCQ1NRX1- (wherein Q1 and RX1 are as defined above), -CQ1NRx1O- (wherein Q1 and RX1 are as def ined above), ONRX1CQ1- (wherein Q1 and RX1 are as defined above), - Q2SO2- (wherein Q2 is an oxygen atom or -NRX10- (wherein RX10 represents a hydrogen atom, formyl group, or a C1-6 alkyl group etc., each of which may have one or more substituents)) or -SO2Q2- (wherein Q2 is as defined above), (wherein, provided that RX2 and RX3, and/or RX4 and RX5 may together form a ring, Q3 and Q4 are the same as or different from each other and each represents an oxygen atom, (O)S(O) or NRX10 (wherein NRX10 is as defined above)); Y represents a 5- to 14-membered aromatic group etc., which may have one or more substituents and one or more hetero atoms; and the ring Z represents a 5-to 14-membered aromatic group which may have 0 to 4 substituents and one or more hetero atoms, and wherein part of the ring may be saturated.
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- CARBOXYLIC ACIDS
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The present invention provides a novel carboxylic acid derivative, a salt thereof or a hydrate of them which is useful as an insulin sensitizer, and a medicament comprising the derivative as the effective ingredient. More specifically, it provides a carboxylic acid compound represented by the formula (I), a salt thereof or a hydrate of them. In the formula, Ar represents a 6- to 14-membered aromatic ring group which may have at least one substituent; R1, R2, R3, R4, R5, R6, R7 and R8 are the same as or different from each other and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a C1-6 alkyl group or a C1-6 alkoxy group; X represents an oxygen atom or a methylene group; Y represents a group represented by the formula (II) or (III): (wherein Z represents a group represented by the formula (IV): (wherein R9, R10, R11 and R12 are the same as or different from each other and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a C1-6 alkyl group or a C1-6 alkoxy group)); m is 0 or 1; and n is 0 or 1.
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- New macrocyclic ligands. VIII di- and tri-linked macrocyclic systems incorporating N2O2-donor atoms
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The synthesis and characterization of new lipophilic di- and tri-linked O2N2-donor macrocycles is reported. The synthesis of the dilinked species involved the initial alkylation of one secondary nitrogen of the parent 15-membered, O
- Atkinson, Ian M.,Boghai, Davar M.,Ghanbari, Bahram,Lindoy, Leonard F.,Meehan, George V.,Saini, Vinod
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p. 351 - 358
(2007/10/03)
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