Property activity refinement of 2-anilino 4-amino substituted quinazolines as antimalarials with fast acting asexual parasite activity

被引：16

作者：

Ashton, Trent D. ^{[1
,2
]}

Ngo, Anna ^{[1
,2
]}

Favuzza, Paola ^{[1
,2
]}

Bullen, Hayley E. ^{[3
,4
]}

Gancheva, Maria R. ^{[6
]}

Romeo, Ornella ^{[6
]}

Schneider, Molly Parkyn ^{[3
,4
]}

Nguyen, Nghi ^{[1
,2
]}

Steel, Ryan W. J. ^{[1
,2
]}

Duffy, Sandra ^{[5
]}

Lowes, Kym N. ^{[1
,2
]}

Sabroux, Helene Jousset ^{[1
,2
]}

Avery, Vicky M. ^{[5
]}

Boddey, Justin A. ^{[1
,2
]}

Wilson, Danny W. ^{[6
]}

Cowman, Alan F. ^{[1
,2
]}

Gilson, Paul R. ^{[3
,4
]}

Sleebs, Brad E. ^{[1
,2
]}

机构：

[1] Walter & Eliza Hall Inst Med Res, 1G Royal Parade, Parkville, Vic 3052, Australia

[2] Univ Melbourne, Dept Med Biol, Parkville, Vic 3010, Australia

[3] Macfarlane Burnet Inst Med Res & Publ Hlth, Melbourne, Vic 3004, Australia

[4] Monash Univ, Clayton, Vic, Australia

[5] Griffith Univ, Griffith Inst Drug Discovery, Discovery Biol, Nathan, Qld 4111, Australia

[6] Univ Adelaide, Sch Biol Sci, Res Ctr Infect Dis, Adelaide, SA, Australia

来源：

BIOORGANIC CHEMISTRY | 2021年 / 117卷

基金：

澳大利亚国家健康与医学研究理事会; 英国医学研究理事会;

关键词：

Malaria; Plasmodium; Antimalarial; Quinazoline; PLASMODIUM-FALCIPARUM; ARTEMISININ RESISTANCE; MALARIA; INHIBITORS; AGENTS; DRUGS; GENE;

D O I：

10.1016/j.bioorg.2021.105359

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：

Malaria is a devastating disease caused by Plasmodium parasites. Emerging resistance against current antimalarial therapeutics has engendered the need to develop antimalarials with novel structural classes. We recently described the identification and initial optimization of the 2-anilino quinazoline antimalarial class. Here, we refine the physicochemical properties of this antimalarial class with the aim to improve aqueous solubility and metabolism and to reduce adverse promiscuity. We show the physicochemical properties of this class are intricately balanced with asexual parasite activity and human cell cytotoxicity. Structural modifications we have implemented improved LipE, aqueous solubility and in vitro metabolism while preserving fast acting P. falciparum asexual stage activity. The lead compounds demonstrated equipotent activity against P. knowlesi parasites and were not predisposed to resistance mechanisms of clinically used antimalarials. The optimized compounds exhibited modest activity against early-stage gametocytes, but no activity against pre-erythrocytic liver parasites. Confoundingly, the refined physicochemical properties installed in the compounds did not engender improved oral efficacy in a P. berghei mouse model of malaria compared to earlier studies on the 2-anilino quinazoline class. This study provides the framework for further development of this antimalarial class.

引用

页数：28

共 36 条

[11] An improved SYBR Green-1-based fluorescence method for the routine monitoring of Plasmodium falciparum resistance to anti-malarial drugs [J].

Dery, Victor ;

Duah, Nancy O. ;

Ayanful-Torgby, Ruth ;

Matrevi, Sena A. ;

Anto, Francis ;

Quashie, Neils B. .

MALARIA JOURNAL, 2015, 14

[12] Identification of inhibitors that dually target the new permeability pathway and dihydroorotate dehydrogenase in the blood stage of Plasmodium falciparum [J].

Dickerman, Benjamin K. ;

Elsworth, Brendan ;

Cobbold, Simon A. ;

Nie, Catherine Q. ;

McConville, Malcolm J. ;

Crabb, Brendan S. ;

Gilson, Paul R. .

SCIENTIFIC REPORTS, 2016, 6

[13] Large-scale production of Plasmodium falciparum gametocytes for malaria drug discovery [J].

Duffy, Sandra ;

Loganathan, Sasdekumar ;

Holleran, John P. ;

Avery, Vicky M. .

NATURE PROTOCOLS, 2016, 11 (05) :976-992

[14] Identification of inhibitors of Plasmodium falciparum gametocyte development [J].

Duffy, Sandra ;

Avery, Vicky M. .

MALARIA JOURNAL, 2013, 12

[15] Dual Plasmepsin-Targeting Antimalarial Agents Disrupt Multiple Stages of the Malaria Parasite Life Cycle [J].

Favuzza, Paola ;

Ruiz, Manuel de Lera ;

Thompson, Jennifer K. ;

Triglia, Tony ;

Ngo, Anna ;

Steel, Ryan W. J. ;

Vavrek, Marissa ;

Christensen, Janni ;

Healer, Julie ;

Boyce, Christopher ;

Guo, Zhuyan ;

Hu, Mengwei ;

Khan, Tanweer ;

Murgolo, Nicholas ;

Zhao, Lianyun ;

Penington, Jocelyn Sietsma ;

Reaksudsan, Kitsanapong ;

Jarman, Kate ;

Dietrich, Melanie H. ;

Richardson, Lachlan ;

Guo, Kai-Yuan ;

Lopaticki, Sash ;

Tham, Wai-Hong ;

Rottmann, Matthias ;

Papenfuss, Tony ;

Robbins, Jonathan A. ;

Boddey, Justin A. ;

Sleebs, Brad E. ;

Sabroux, Helene Jousset ;

McCauley, John A. ;

Olsen, David B. ;

Cowman, Alan F. .

CELL HOST & MICROBE, 2020, 27 (04) :642-+

[16] SEVERAL ALLELES OF THE MULTIDRUG-RESISTANCE GENE ARE CLOSELY LINKED TO CHLOROQUINE RESISTANCE IN PLASMODIUM-FALCIPARUM [J].

FOOTE, SJ ;

KYLE, DE ;

MARTIN, RK ;

ODUOLA, AMJ ;

FORSYTH, K ;

KEMP, DJ ;

COWMAN, AF .

NATURE, 1990, 345 (6272) :255-258

[17] A Plasmodium berghei reference line that constitutively expresses GFP at a high level throughout the complete life cycle [J].

Franke-Fayard, B ;

Trueman, H ;

Ramesar, J ;

Mendoza, J ;

van der Keur, M ;

van der Linden, R ;

Sinden, RE ;

Waters, AP ;

Janse, CJ .

MOLECULAR AND BIOCHEMICAL PARASITOLOGY, 2004, 137 (01) :23-33

[18] Evaluation of 4-Amino 2-Anilinoquinazolines against Plasmodium and Other Apicomplexan Parasites In Vitro and in a P. falciparum Humanized NOD-scid IL2Rγnull Mouse Model of Malaria [J].

Gilson, Paul R. ;

Nguyen, William ;

Poole, William A. ;

Teixeira, Jose E. ;

Thompson, Jennifer K. ;

Guo, Kaiyuan ;

Stewart, Rebecca J. ;

Ashton, Trent D. ;

White, Karen L. ;

Sanz, Laura M. ;

Gamo, Francisco-Javier ;

Charman, Susan A. ;

Wittlin, Sergio ;

Duffy, James ;

Tonkin, Christopher J. ;

Tham, Wai-Hong ;

Crabb, Brendan S. ;

Cooke, Brian M. ;

Huston, Christopher D. ;

Cowman, Alan F. ;

Sleebs, Brad E. .

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2019, 63 (03)

[19] Optimization of 2-Anilino 4-Amino Substituted Quinazolines into Potent Antimalarial Agents with Oral in Vivo Activity [J].

Gilson, Paul R. ;

Tan, Cyrus ;

Jarman, Kate E. ;

Lowes, Kym N. ;

Curtis, Joan M. ;

Nguyen, William ;

Di Rago, Adrian E. ;

Bullen, Hayley E. ;

Prinz, Boris ;

Duffy, Sandra ;

Baell, Jonathan B. ;

Hutton, Craig A. ;

Subroux, Helene Jousset ;

Crabb, Brendan S. ;

Avery, Vicky M. ;

Cowman, Alan F. ;

Sleebs, Brad E. .

JOURNAL OF MEDICINAL CHEMISTRY, 2017, 60 (03) :1171-1188

[20] Triaminopyrimidine is a fast-killing and long-acting antimalarial clinical candidate [J].

Hameed, Shahul P. ;

Solapure, Suresh ;

Patil, Vikas ;

Henrich, Philipp P. ;

Magistrado, Pamela A. ;

Bharath, Sowmya ;

Murugan, Kannan ;

Viswanath, Pavithra ;

Puttur, Jayashree ;

Srivastava, Abhishek ;

Bellale, Eknath ;

Panduga, Vijender ;

Shanbag, Gajanan ;

Awasthy, Disha ;

Landge, Sudhir ;

Morayya, Sapna ;

Koushik, Krishna ;

Saralaya, Ramanatha ;

Raichurkar, Anandkumar ;

Rautela, Nikhil ;

Choudhury, Nilanjana Roy ;

Ambady, Anisha ;

Nandishaiah, Radha ;

Reddy, Jitendar ;

Prabhakar, K. R. ;

Menasinakai, Sreenivasaiah ;

Rudrapatna, Suresh ;

Chatterji, Monalisa ;

Belen Jimenez-Diaz, Maria ;

Santos Martinez, Maria ;

Maria Sanz, Laura ;

Coburn-Flynn, Olivia ;

Fidock, David A. ;

Lukens, Amanda K. ;

Wirth, Dyann F. ;

Bandodkar, Balachandra ;

Mukherjee, Kakoli ;

McLaughlin, Robert E. ;

Waterson, David ;

Rosenbrier-Ribeiro, Lyn ;

Hickling, Kevin ;

Balasubramanian, V. ;

Warner, Peter ;

Hosagrahara, Vinayak ;

Dudley, Adam ;

Iyer, Pravin S. ;

Narayanan, Shridhar ;

Kavanagh, Stefan ;

Sambandamurthy, Vasan K. .

NATURE COMMUNICATIONS, 2015, 6

← 1 2 3 4 →