Flexible 2,4-diaminopyrimidine bearing a butyrolactone as Plasmodium falciparum dihydrofolate reductase inhibitors

被引:0
作者
Decharuangsilp, Sasithorn [1 ]
Arwon, Uthai [1 ]
Hoarau, Marie [1 ]
Vanichtanankul, Jarunee [1 ]
Saeyang, Thanaya [1 ]
Jantra, Tararat [1 ]
Rattanajak, Roonglawan [1 ]
Thiabma, Ratthiya [1 ]
Sooksai, Nawarat [1 ]
Kongkasuriyachai, Darin [1 ]
Kamchonwongpaisan, Sumalee [1 ]
Yuthavong, Yongyuth [1 ]
机构
[1] Natl Sci & Technol Dev Agcy NSTDA, Natl Ctr Genet Engn & Biotechnol BIOTEC, 113 Thailand Sci Pk, Khlong Luang 12120, Pathum Thani, Thailand
关键词
Antimalarial; Plasmodium falciparum; DHFR; Flexible diaminopyrimidine; Butyrolactone; MALARIAL DIHYDROFOLATE-REDUCTASE; FALCIPARUM; RESISTANCE; PYRIMETHAMINE; DYNAMICS; MUTANTS;
D O I
10.1016/j.bioorg.2024.107789
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Recently, P218, a new flexible antifolate targeting Plasmodium falciparum dihydrofolate reductase (PfDHFR), has entered its clinical trial with good safety profile and effective Pf infection prevention. However, it carries a free carboxyl terminal, which is hydrophilic and prone to metabolic glucuronidation. Here, a new series of P218 analogues carrying butyrolactone has been synthesized with the purpose of enhancing lipophilicity and minimizing metabolic instability. The inhibition constants against the mutant PfDHFR enzymes are in sub-nanomolar level and the antimalarial activity against antifolate-resistant parasites are in the low micromolar range. The crystal structure of the most potent analogue LA1 bound enzyme complex indicates interaction with multiple residues, including Arg122 and Phe116 in the active site. In vitro log D-7.4 and kinetic solubility confirmed a higher lipophilicity of this butyrolactone series as compared to P218. These outcomes suggest the possibility to further develop butyrolactone derivatives as non-carboxyl antiplasmodial antifolates.
引用
收藏
页数:15
相关论文
共 31 条
[1]   Towards automated crystallographic structure refinement with phenix.refine [J].
Afonine, Pavel V. ;
Grosse-Kunstleve, Ralf W. ;
Echols, Nathaniel ;
Headd, Jeffrey J. ;
Moriarty, Nigel W. ;
Mustyakimov, Marat ;
Terwilliger, Thomas C. ;
Urzhumtsev, Alexandre ;
Zwart, Peter H. ;
Adams, Paul D. .
ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY, 2012, 68 :352-367
[2]  
[Anonymous], 2015, The PyMOL Molecular Graphics System
[3]  
[Anonymous], 2022, World Malaria Report 2022
[4]   Evidence of Artemisinin-Resistant Malaria in Africa [J].
Balikagala, Betty ;
Fukuda, Naoyuki ;
Ikeda, Mie ;
Katuro, Osbert T. ;
Tachibana, Shin-Ichiro ;
Yamauchi, Masato ;
Opio, Walter ;
Emoto, Sakurako ;
Anywar, Denis A. ;
Kimura, Eisaku ;
Palacpac, Nirianne M. Q. ;
Odongo-Aginya, Emmanuel, I ;
Ogwang, Martin ;
Horii, Toshihiro ;
Mita, Toshihiro .
NEW ENGLAND JOURNAL OF MEDICINE, 2021, 385 (13) :1163-1171
[5]   ISOLATION OF CLONES OF PLASMODIUM-FALCIPARUM BY MICROMANIPULATION [J].
BEALE, GH ;
THAITHONG, S ;
SIRIPOOL, N .
TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE, 1991, 85 (01) :37-37
[6]   An in vitro toolbox to accelerate anti-malarial drug discovery and development [J].
Charman, Susan A. ;
Andreu, Alice ;
Barker, Helena ;
Blundell, Scott ;
Campbell, Anna ;
Campbell, Michael ;
Chen, Gong ;
Chiu, Francis C. K. ;
Crighton, Elly ;
Katneni, Kasiram ;
Morizzi, Julia ;
Patil, Rahul ;
Thao Pham ;
Ryan, Eileen ;
Saunders, Jessica ;
Shackleford, David M. ;
White, Karen L. ;
Almond, Lisa ;
Dickins, Maurice ;
Smith, Dennis A. ;
Moehrle, Joerg J. ;
Burrows, Jeremy N. ;
Abla, Nada .
MALARIA JOURNAL, 2020, 19 (01)
[7]   First-in-human clinical trial to assess the safety, tolerability and pharmacokinetics of P218, a novel candidate for malaria chemoprotection [J].
Chughlay, M. Farouk ;
Rossignol, Emilie ;
Donini, Cristina ;
El Gaaloul, Myriam ;
Lorch, Ulrike ;
Coates, Simon ;
Langdon, Grant ;
Hammond, Tim ;
Moehrle, Joerg ;
Chalon, Stephan .
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, 2020, 86 (06) :1113-1124
[8]   QUANTITATIVE ASSESSMENT OF ANTI-MALARIAL ACTIVITY INVITRO BY A SEMIAUTOMATED MICRODILUTION TECHNIQUE [J].
DESJARDINS, RE ;
CANFIELD, CJ ;
HAYNES, JD ;
CHULAY, JD .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 1979, 16 (06) :710-718
[9]   Features and development of Coot [J].
Emsley, P. ;
Lohkamp, B. ;
Scott, W. G. ;
Cowtan, K. .
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 2010, 66 :486-501
[10]   Design, Synthesis, and Biological Evaluation of Unconventional Aminopyrimidine, Aminopurine, and Amino-1,3,5-triazine Methyloxynucleosides [J].
Fernandez-Cureses, Gloria ;
de Castro, Sonia ;
Jimeno, Maria-Luisa ;
Balzarini, Jan ;
Camarasa, Maria-Jose .
CHEMMEDCHEM, 2015, 10 (02) :321-335