2,4-Diaminothienopyrimidines as Orally Active Antimalarial Agents

• Published in: Journal of medicinal chemistry Vol. 57; no. 3; pp. 1014 - 1022
• Main Authors: González Cabrera, Diego, Le Manach, Claire, Douelle, Frederic, Younis, Yassir, Feng, Tzu-Shean, Paquet, Tanya, Nchinda, Aloysius T, Street, Leslie J, Taylor, Dale, de Kock, Carmen, Wiesner, Lubbe, Duffy, Sandra, White, Karen L, Zabiulla, K. Mohammed, Sambandan, Yuvaraj, Bashyam, Sridevi, Waterson, David, Witty, Michael J, Charman, Susan A, Avery, Vicky M, Wittlin, Sergio, Chibale, Kelly
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 13.02.2014; Amer Chemical Soc
• Subjects: Administration, Oral; Animals; Antimalarials - chemical synthesis; Antimalarials - chemistry; Antimalarials - pharmacology; Cell Line; Chemistry, Medicinal; Databases, Chemical; Drug Resistance, Multiple; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels - antagonists & inhibitors; High-Throughput Screening Assays; Humans; Life Sciences & Biomedicine; Malaria - drug therapy; Malaria - parasitology; Male; Mice; Microsomes, Liver - metabolism; Pharmacology & Pharmacy; Plasmodium berghei; Plasmodium falciparum - drug effects; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Rats; Rats, Sprague-Dawley; Science & Technology; Structure-Activity Relationship; Thiophenes - chemical synthesis; Thiophenes - chemistry; Thiophenes - pharmacology; PYRIMIDINES; ANTIPLASMODIAL ACTIVITY; MALARIA; CROSS-COUPLING REACTIONS; SINGLE-DOSE CURE; DERIVATIVES
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm401760c

A novel series of 2,4-diaminothienopyrimidines with potential as antimalarials was identified from whole-cell high-throughput screening of a SoftFocus ion channel library. Synthesis and structure–activity relationship studies identified compounds with potent antiplasmodial activity and low in vitro cytotoxicity. Several of these analogues exhibited in vivo activity in the Plasmodium berghei mouse model when administered orally. However, inhibition of the hERG potassium channel was identified as a liability for this series.