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Synthesis, Structure–Activity Relationship, and Antimalarial Activity of Ureas and Thioureas of 15-Membered Azalides


Bukvić Krajačić, Mirjana: Perić, Mihaela; Smith, Kirsten S.; Ivezić Schonfeld, Zrinka; Žiher, Dinko; Fajdetić, Andreja; Kujundžić, Nedjeljko; Schonfeld, Wolfgang; Landek, Goran; Padovan, Jasna; Jelić, Dubravko et al.
Synthesis, Structure–Activity Relationship, and Antimalarial Activity of Ureas and Thioureas of 15-Membered Azalides // Journal of medicinal chemistry, 54 (2011), 10; 3595-3605 doi:10.1021/jm2001585 (međunarodna recenzija, članak, znanstveni)


Naslov
Synthesis, Structure–Activity Relationship, and Antimalarial Activity of Ureas and Thioureas of 15-Membered Azalides

Autori
Bukvić Krajačić, Mirjana: Perić, Mihaela ; Smith, Kirsten S. ; Ivezić Schonfeld, Zrinka ; Žiher, Dinko ; Fajdetić, Andreja ; Kujundžić, Nedjeljko ; Schonfeld, Wolfgang ; Landek, Goran ; Padovan, Jasna ; Jelić, Dubravko ; Ager, ArbaMilhous, Wilbur K. ; Ellis, William ; Spaventi, Radan ; Ohrt, Colin

Izvornik
Journal of medicinal chemistry (0022-2623) 54 (2011), 10; 3595-3605

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
SAR; antimalarial acivity; urea; thiourea; azalides

Sažetak
Azithromycin, a first member of the azalide family of macrolides, while having substantial antimalarial activity, failed as a single agent for malaria prophylaxis. In this paper we present the first analogue campaign to identify more potent compounds from this class. Ureas and thioureas of 15-membered azalides, N′′-substituted 9a-(N′-carbamoyl-β-aminoethyl), 9a-(N′- thiocarbamoyl-β-aminoethyl), 9a-[N′-(β- cyanoethyl)-N′-(carbamoyl-β-aminoethyl)], 9a-[N′- (β-cyanoethyl)-N′-(thiocarbamoyl-β-aminoethyl)], 9a-{; ; ; ; N′-[β-(ethoxycarbonyl)ethyl]-N′(carbamoyl-β- aminoethyl)}; ; ; ; , and 9a-[N′-(β-amidoethyl)-N′- (carbamoyl-β-aminoethyl)] of 9-deoxo-9-dihydro-9a- aza-9a-homoerythromycin A, were synthesized and their biological properties evaluated. The results obtained indicate a substantial improvement of the in vitro activity against P. falciparum (up to 88 times over azithromycin), particularly for compounds containing both sugars on the macrocyclic ring and aromatic moiety on 9a- position. The improved in vitro activity was not confirmed in the mouse model, likely due to an increase in lipophilicity of these analogues leading to a higher volume of distribution. Overall, with increased in vitro activity, promising PK properties, and modest in vivo efficacy, this series of molecules represents a good starting platform for the design of novel antimalarial azalides.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Farmacija



POVEZANOST RADA


Projekt / tema
006-0000000-3216 - Sinteza, karakterizacija i djelovanje potencijalnih i poznatih ljekovitih tvari (Branka Zorc, )

Ustanove
Farmaceutsko-biokemijski fakultet, Zagreb

Citiraj ovu publikaciju

Bukvić Krajačić, Mirjana: Perić, Mihaela; Smith, Kirsten S.; Ivezić Schonfeld, Zrinka; Žiher, Dinko; Fajdetić, Andreja; Kujundžić, Nedjeljko; Schonfeld, Wolfgang; Landek, Goran; Padovan, Jasna; Jelić, Dubravko et al.
Synthesis, Structure–Activity Relationship, and Antimalarial Activity of Ureas and Thioureas of 15-Membered Azalides // Journal of medicinal chemistry, 54 (2011), 10; 3595-3605 doi:10.1021/jm2001585 (međunarodna recenzija, članak, znanstveni)
Bukvić Krajačić, Mirjana: Perić, Mihaela, Smith, K., Ivezić Schonfeld, Z., Žiher, D., Fajdetić, A., Kujundžić, N., Schonfeld, W., Landek, G., Padovan, J. & Jelić, D. (2011) Synthesis, Structure–Activity Relationship, and Antimalarial Activity of Ureas and Thioureas of 15-Membered Azalides. Journal of medicinal chemistry, 54 (10), 3595-3605 doi:10.1021/jm2001585.
@article{article, year = {2011}, pages = {3595-3605}, DOI = {10.1021/jm2001585}, keywords = {SAR, antimalarial acivity, urea, thiourea, azalides}, journal = {Journal of medicinal chemistry}, doi = {10.1021/jm2001585}, volume = {54}, number = {10}, issn = {0022-2623}, title = {Synthesis, Structure–Activity Relationship, and Antimalarial Activity of Ureas and Thioureas of 15-Membered Azalides}, keyword = {SAR, antimalarial acivity, urea, thiourea, azalides} }

Časopis indeksira:


  • Current Contents Connect (CCC)
  • Web of Science Core Collection (WoSCC)
    • Science Citation Index Expanded (SCI-EXP)
    • SCI-EXP, SSCI i/ili A&HCI
  • Scopus
  • MEDLINE


Uključenost u ostale bibliografske baze podataka:


  • CA Search (Chemical Abstracts)
  • EMBASE (Excerpta Medica)
  • MEDLINE


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