Incorporation of an intramolecular hydrogen-bonding motif in the side chain of 4-aminoquinolines enhances activity against drug-resistant P-falciparum

Madrid PB; Liou AP; DeRisi JL; Guy RK

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Incorporation of an intramolecular hydrogen-bonding motif in the side chain of 4-aminoquinolines enhances activity against drug-resistant P-falciparum

机译：在4-氨基喹啉的侧链中掺入分子内氢键基序可增强抗药性恶性疟原虫的活性

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Previous data showing that several chloroquine analogues containing an intramolecular hydrogen-bonding motif were potent against multidrug-resistant P. falciparum led to the exploration of the importance of this motif. A series of 116 compounds containing four different alkyl linkers and various aromatic substitutions with hydrogen bond accepting capability was synthesized. The series showed broad potency against the drug-resistant W2 strain of P. falciparum. In particular, a novel series containing variations of the alpha-aminocresol motif gave eight compounds with IC50 values more potent than 5 nM against the W2 strain. Such simple modifications, significantly altering the pK(a) and sterics of the basic side chain in chloroquine analogues, may prove to be part of a strategy for overcoming the problem of worldwide resistance to affordable antimalarial drugs.

机译：先前的数据表明，几种含有分子内氢键基序的氯喹类似物对耐多药恶性疟原虫具有强大的作用，这导致人们对该基序的重要性进行了探索。合成了116种包含四个不同烷基连接基和具有氢键接受能力的各种芳族取代基的化合物。该系列药物对恶性疟原虫的W2耐药菌株具有广泛的效力。特别是，一个包含α-氨基甲酚基序变异的新系列化合物，对W2菌株产生的IC50值比5 nM更有效的八种化合物。这种简单的修饰可显着改变氯喹类似物基本侧链的pK（a）和位阻，可能是克服全球范围内对可负担得起的抗疟药耐药性问题的策略的一部分。

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《Journal of Medicinal Chemistry》 |2006年第15期|共9页
作者
Madrid PB; Liou AP; DeRisi JL; Guy RK;
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正文语种 eng
中图分类药学;
关键词
CHLOROQUINE RESISTANCE; MALARIA PARASITES; ANTIHYPERTENSIVE ACTIVITY; PFCRT; ANTIMALARIALS; TRANS-4-AMINO-3; 4-DIHYDRO-2; 2-DIMETHYL-2H-1-BENZOPYRAN-3-OLS; PERSPECTIVE; TRANSPORTER; MECHANISMS; MUTATIONS;

机译：耐氯离子性;疟疾寄生虫;抗高血压活性;PFCRT;抗疟药;TRANS-4-氨基-3;4-二氢-2;2-二甲基-2H-1-苯并吡喃-3-OLS;透视;转运剂;机理;突变;

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1. Incorporation of an intramolecular hydrogen-bonding motif in the side chain of 4-aminoquinolines enhances activity against drug-resistant P-falciparum [J] . Madrid PB, Liou AP, DeRisi JL, Journal of Medicinal Chemistry . 2006,第15期

机译：在4-氨基喹啉的侧链中掺入分子内氢键基序可增强抗药性恶性疟原虫的活性
2. Incorporation of Fluorinated Pyridine in the Side Chain of 4-Aminoquinolines: Synthesis, Characterization and Antibacterial Activity [J] . Reza Ranjbar-Karimi, Alireza Poorfreidoni Drug research . 2018,第1期

机译：在4-氨基喹啉的侧链中掺入氟化吡啶：合成，表征和抗菌活性
3. Incorporation of an intramolecular hydrogen bonding motif in the side chain of antimalarial benzimidazoles [J] . Henrietta D. Attram, Sergio Wittlin, Kelly Chibale MedChemComm . 2019,第3期

机译：掺入抗体苯并咪唑侧链中的分子内氢键基序
4. Enhancing Motif Refinement by Incorporating Comparative Genomics Data [C] . Erliang Zeng, Giri Narasimhan Bioinformatics Research and Applications; Lecture Notes in Bioinformatics; 4463 . 2007

机译：通过整合比较基因组学数据来增强母题精炼
5. Antimicrobial and Cytotoxic Activities of Short Chain Fatty Acids Against Drug-Resistant Staphylococcus aureus [D] . Sierra, Maria Cecilia. 2017

机译：短链脂肪酸对耐药金黄色葡萄球菌的抗菌和细胞毒活性
6. Incorporation of an Intramolecular Hydrogen-bonding Motif in the Side-Chain of 4-Aminoquinolines Enhances Activity against Drug-Resistant P. falciparum [O] . Peter B. Madrid, Ally P. Liou, Joseph L. DeRisi, -1

机译：在4-氨基喹啉侧链中掺入分子内氢键基序增强了抗药性恶性疟原虫的活性
7. Incorporation of an Intramolecular Hydrogen-Bonding Motif in the Side Chain of 4-Aminoquinolines Enhances Activity against Drug-Resistant P. falciparum [O] . Peter B. Madrid, Ally P. Liou, Joseph L. DeRisi, 2008

机译：在4-氨基喹啉的侧链中掺入分子内氢键基序，增强了耐药性P. falciparum的活性

Incorporation of an intramolecular hydrogen-bonding motif in the side chain of 4-aminoquinolines enhances activity against drug-resistant P-falciparum

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