Lead Optimization of Imidazopyrazines: a New Class of Antimalarial with Activity on Plasmodium Liver Stages

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2014 Aug 23

PMID 25147620

Citations 12

Authors

Bin Zou

Advait Nagle

Arnab K Chatterjee

Seh Yong Leong

Liying Jocelyn Tan

Wei Lin Sandra Sim

Pranab Mishra

Prasuna Guntapalli

David C Tully

Suresh B Lakshminarayana

Chek Shik Lim

Yong Cheng Tan

Siti Nurdiana Abas

Christophe Bodenreider

Kelli L Kuhen

Kerstin Gagaring

Rachel Borboa

Jonathan Chang

Chun Li

Thomas Hollenbeck

Tove Tuntland

Anne-Marie Zeeman

Clemens H M Kocken

Case McNamara

Nobutaka Kato

Elizabeth A Winzeler

Bryan K S Yeung

Thierry T Diagana

Paul W Smith

Jason Roland

Affiliations

Soon will be listed here.

Abstract

Imidazopyridine 1 was identified from a phenotypic screen against P. falciparum (Pf) blood stages and subsequently optimized for activity on liver-stage schizonts of the rodent parasite P. yoelii (Py) as well as hypnozoites of the simian parasite P. cynomolgi (Pc). We applied these various assays to the cell-based lead optimization of the imidazopyrazines, exemplified by 3 (KAI407), and show that optimized compounds within the series with improved pharmacokinetic properties achieve causal prophylactic activity in vivo and may have the potential to target the dormant stages of P. vivax malaria.

Citing Articles

Oxidative Stress and Chronic Myeloid Leukemia: A Balance between ROS-Mediated Pro- and Anti-Apoptotic Effects of Tyrosine Kinase Inhibitors.

Allegra A, Mirabile G, Caserta S, Stagno F, Russo S, Pioggia G Antioxidants (Basel). 2024; 13(4).

PMID: 38671909 PMC: 11047441. DOI: 10.3390/antiox13040461.

Imidazolopiperazine (IPZ)-Induced Differential Transcriptomic Responses on Wild-Type and IPZ-Resistant Mutant Parasites.

Dembele L, Dara A, Maiga M, Maiga F, Cissoko D, Djimde A Genes (Basel). 2023; 14(12).

PMID: 38136946 PMC: 10743112. DOI: 10.3390/genes14122124.

Selenylated Imidazo[1,2]pyridine Induces Cell Senescence and Oxidative Stress in Chronic Myeloid Leukemia Cells.

Burkner G, Dias D, Souza de Souza K, de Araujo A, Luiz Soares Basilio D, Jacobsen F Molecules. 2023; 28(2).

PMID: 36677949 PMC: 9860887. DOI: 10.3390/molecules28020893.

An Update on Development of Small-Molecule Plasmodial Kinase Inhibitors.

Moolman C, van der Sluis R, Beteck R, Legoabe L Molecules. 2020; 25(21).

PMID: 33171706 PMC: 7664427. DOI: 10.3390/molecules25215182.

Malaria and tuberculosis as diseases of neglected populations: state of the art in chemotherapy and advances in the search for new drugs.

de Araujo R, Santos S, Sanches L, Giarolla J, El Seoud O, Ferreira E Mem Inst Oswaldo Cruz. 2020; 115:e200229.

PMID: 33053077 PMC: 7534959. DOI: 10.1590/0074-02760200229.

References

Mendis K, Sina B, Marchesini P, Carter R . The neglected burden of Plasmodium vivax malaria. Am J Trop Med Hyg. 2001; 64(1-2 Suppl):97-106. DOI: 10.4269/ajtmh.2001.64.97. View

Meister S, Plouffe D, Kuhen K, Bonamy G, Wu T, Barnes S . Imaging of Plasmodium liver stages to drive next-generation antimalarial drug discovery. Science. 2011; 334(6061):1372-7. PMC: 3473092. DOI: 10.1126/science.1211936. View

Dembele L, Franetich J, Lorthiois A, Gego A, Zeeman A, Kocken C . Persistence and activation of malaria hypnozoites in long-term primary hepatocyte cultures. Nat Med. 2014; 20(3):307-12. DOI: 10.1038/nm.3461. View

Schmidt L . Appraisals of compounds of diverse chemical classes for capacities to cure infections with sporozoites of Plasmodium cynomolgi. Am J Trop Med Hyg. 1983; 32(2):231-57. DOI: 10.4269/ajtmh.1983.32.231. View

ALVING A, Carson P, Flanagan C, ICKES C . Enzymatic deficiency in primaquine-sensitive erythrocytes. Science. 1956; 124(3220):484-5. DOI: 10.1126/science.124.3220.484-a. View

Plouffe D, Brinker A, McNamara C, Henson K, Kato N, Kuhen K . In silico activity profiling reveals the mechanism of action of antimalarials discovered in a high-throughput screen. Proc Natl Acad Sci U S A. 2008; 105(26):9059-64. PMC: 2440361. DOI: 10.1073/pnas.0802982105. View

Hay S, Guerra C, Tatem A, Noor A, Snow R . The global distribution and population at risk of malaria: past, present, and future. Lancet Infect Dis. 2004; 4(6):327-36. PMC: 3145123. DOI: 10.1016/S1473-3099(04)01043-6. View

Chezal J, Moreau E, Delmas G, Gueiffier A, Blache Y, Grassy G . Heterocyclization of functionalized vinylic derivatives of imidazo. J Org Chem. 2001; 66(20):6576-84. DOI: 10.1021/jo015582x. View

Zeeman A, van Amsterdam S, McNamara C, Voorberg-van der Wel A, Klooster E, van den Berg A . KAI407, a potent non-8-aminoquinoline compound that kills Plasmodium cynomolgi early dormant liver stage parasites in vitro. Antimicrob Agents Chemother. 2013; 58(3):1586-95. PMC: 3957848. DOI: 10.1128/AAC.01927-13. View

10.

White N . Plasmodium knowlesi: the fifth human malaria parasite. Clin Infect Dis. 2008; 46(2):172-3. DOI: 10.1086/524889. View

11.

Mueller I, Galinski M, Baird J, Carlton J, Kochar D, Alonso P . Key gaps in the knowledge of Plasmodium vivax, a neglected human malaria parasite. Lancet Infect Dis. 2009; 9(9):555-66. DOI: 10.1016/S1473-3099(09)70177-X. View

12.

McNamara C, Lee M, Lim C, Lim S, Roland J, Simon O . Targeting Plasmodium PI(4)K to eliminate malaria. Nature. 2013; 504(7479):248-253. PMC: 3940870. DOI: 10.1038/nature12782. View