Hit-to-Lead Studies for the Antimalarial Tetrahydroisoquinolone Carboxanilides

David M. Floyd, Philip Stein, Zheng Wang, Jian Liu, Steve Castro, Julie A. Clark, Michele Connelly, Fangyi Zhu, Gloria Holbrook, Amy Matheny, Martina S. Sigal, Jaeki Min, Rajkumar Dhinakaran, Senthil Krishnan, Sridevi Bashyum, Spencer Knapp, R. Kiplin Guy

Research output: Contribution to journalArticlepeer-review

38 Scopus citations


Phenotypic whole-cell screening in erythrocytic cocultures of Plasmodium falciparum identified a series of dihydroisoquinolones that possessed potent antimalarial activity against multiple resistant strains of P. falciparum in vitro and show no cytotoxicity to mammalian cells. Systematic structure-activity studies revealed relationships between potency and modifications at N-2, C-3, and C-4. Careful structure-property relationship studies, coupled with studies of metabolism, addressed the poor aqueous solubility and metabolic vulnerability, as well as potential toxicological effects, inherent in the more potent primary screening hits such as 10b. Analogues 13h and 13i, with structural modifications at each site, were shown to possess excellent antimalarial activity in vivo. The (+)-(3S,4S) enantiomer of 13i and similar analogues were identified as the more potent. On the basis of these studies, we have selected (+)-13i for further study as a preclinical candidate.

Original languageEnglish
Pages (from-to)7950-7962
Number of pages13
JournalJournal of Medicinal Chemistry
Issue number17
StatePublished - Sep 8 2016

Bibliographical note

Funding Information:
We are grateful to the NIH (AI090662), the Medicines for Malaria Venture (MMV), and the American Lebanese Syrian Associated Charities (ALSAC) for financial support, and to Jayan Joseph and Yuvaraj Sambandan for experimental assistance.

Publisher Copyright:
© 2016 American Chemical Society.

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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