Antimalarial activity of 9a-N substituted 15-membered azalides with improved in vitro and in vivo activity over azithromycin

Mihaela Perić, Andrea Fajdetić, Renata Rupčić, Sulejman Alihodžić, Dinko Žiher, Mirjana Bukvić Krajačić, Kirsten S. Smith, Zrinka Ivezić-Schönfeld, Jasna Padovan, Goran Landek, Dubravko Jelić, Antun Hutinec, Milan Mesić, Arba L Ager, William Y. Ellis, Wilbur K. Milhous, Colin Ohrt, Radan Spaventi

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Novel classes of antimalarial drugs are needed due to emerging drug resistance. Azithromycin, the first macrolide investigated for malaria treatment and prophylaxis, failed as a single agent and thus novel analogues were envisaged as the next generation with improved activity. We synthesized 42 new 9a-N substituted 15-membered azalides with amide and amine functionalities via simple and inexpensive chemical procedures using easily available building blocks. These compounds exhibited marked advances over azithromycin in vitro in terms of potency against Plasmodium falciparum (over 100-fold) and high selectivity for the parasite and were characterized by moderate oral bioavailability in vivo. Two amines and one amide derivative showed improved in vivo potency in comparison to azithromycin when tested in a mouse efficacy model. Results obtained for compound 6u, including improved in vitro potency, good pharmacokinetic parameters, and in vivo efficacy higher than azithromycin and comparable to chloroquine, warrant its further development for malaria treatment and prophylaxis.

Original languageEnglish (US)
Pages (from-to)1389-1401
Number of pages13
JournalJournal of Medicinal Chemistry
Volume55
Issue number3
DOIs
StatePublished - Feb 9 2012

Fingerprint

Azithromycin
Antimalarials
Amides
Malaria
Amines
Macrolides
Chloroquine
Plasmodium falciparum
Drug Resistance
Biological Availability
Parasites
Pharmacokinetics
In Vitro Techniques

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Perić, M., Fajdetić, A., Rupčić, R., Alihodžić, S., Žiher, D., Bukvić Krajačić, M., ... Spaventi, R. (2012). Antimalarial activity of 9a-N substituted 15-membered azalides with improved in vitro and in vivo activity over azithromycin. Journal of Medicinal Chemistry, 55(3), 1389-1401. https://doi.org/10.1021/jm201615t

Antimalarial activity of 9a-N substituted 15-membered azalides with improved in vitro and in vivo activity over azithromycin. / Perić, Mihaela; Fajdetić, Andrea; Rupčić, Renata; Alihodžić, Sulejman; Žiher, Dinko; Bukvić Krajačić, Mirjana; Smith, Kirsten S.; Ivezić-Schönfeld, Zrinka; Padovan, Jasna; Landek, Goran; Jelić, Dubravko; Hutinec, Antun; Mesić, Milan; Ager, Arba L; Ellis, William Y.; Milhous, Wilbur K.; Ohrt, Colin; Spaventi, Radan.

In: Journal of Medicinal Chemistry, Vol. 55, No. 3, 09.02.2012, p. 1389-1401.

Research output: Contribution to journalArticle

Perić, M, Fajdetić, A, Rupčić, R, Alihodžić, S, Žiher, D, Bukvić Krajačić, M, Smith, KS, Ivezić-Schönfeld, Z, Padovan, J, Landek, G, Jelić, D, Hutinec, A, Mesić, M, Ager, AL, Ellis, WY, Milhous, WK, Ohrt, C & Spaventi, R 2012, 'Antimalarial activity of 9a-N substituted 15-membered azalides with improved in vitro and in vivo activity over azithromycin', Journal of Medicinal Chemistry, vol. 55, no. 3, pp. 1389-1401. https://doi.org/10.1021/jm201615t
Perić, Mihaela ; Fajdetić, Andrea ; Rupčić, Renata ; Alihodžić, Sulejman ; Žiher, Dinko ; Bukvić Krajačić, Mirjana ; Smith, Kirsten S. ; Ivezić-Schönfeld, Zrinka ; Padovan, Jasna ; Landek, Goran ; Jelić, Dubravko ; Hutinec, Antun ; Mesić, Milan ; Ager, Arba L ; Ellis, William Y. ; Milhous, Wilbur K. ; Ohrt, Colin ; Spaventi, Radan. / Antimalarial activity of 9a-N substituted 15-membered azalides with improved in vitro and in vivo activity over azithromycin. In: Journal of Medicinal Chemistry. 2012 ; Vol. 55, No. 3. pp. 1389-1401.
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AU - Ohrt, Colin

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