Design, synthesis, antitrypanosomal activity, DNA/RNA binding and in vitro ADME profiling of novel imidazoline-substituted 2-arylbenzimidazoles

Bistrović Popov, Andrea; Krstulović, Luka; Koštrun, Sanja; Jelić, Dubravko; Bokulić, Ana; Radić Stojković, Marijana; Zonjić, Iva; Taylor, Martin C.; Kelly, John M.; Bajić, Miroslav; Raić-Malić, Silvana

doi:10.1016/j.ejmech.2020.112802

Pregled bibliografske jedinice broj: 1083249

Design, synthesis, antitrypanosomal activity, DNA/RNA binding and in vitro ADME profiling of novel imidazoline-substituted 2- arylbenzimidazoles

Bistrović Popov, Andrea; Krstulović, Luka; Koštrun, Sanja; Jelić, Dubravko; Bokulić, Ana; Radić Stojković, Marijana; Zonjić, Iva; Taylor, Martin C.; Kelly, John M.; Bajić, Miroslav; Raić-Malić, Silvana

Design, synthesis, antitrypanosomal activity, DNA/RNA binding and in vitro ADME profiling of novel imidazoline-substituted 2- arylbenzimidazoles // European journal of medicinal chemistry, 207 (2020), 112802, 19 doi:10.1016/j.ejmech.2020.112802 (međunarodna recenzija, članak, znanstveni)

CROSBI ID: 1083249 Za ispravke kontaktirajte CROSBI podršku putem web obrasca

Naslov
Design, synthesis, antitrypanosomal activity, DNA/RNA binding and in vitro ADME profiling of novel imidazoline-substituted 2- arylbenzimidazoles

Autori
Bistrović Popov, Andrea ; Krstulović, Luka ; Koštrun, Sanja ; Jelić, Dubravko ; Bokulić, Ana ; Radić Stojković, Marijana ; Zonjić, Iva ; Taylor, Martin C. ; Kelly, John M. ; Bajić, Miroslav ; Raić-Malić, Silvana

Izvornik
European journal of medicinal chemistry (0223-5234) 207 (2020); 112802, 19

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

Ključne riječi
Imidazoline-substituted benzimidazole ; ADME ; DNA binding ; Trypanosoma brucei

Sažetak
Novel imidazoline benzimidazole derivatives containing diversely substituted phenoxy moieties were synthesized with the aim of evaluating their antitrypanosomal activity, DNA/RNA binding affinity and in vitro ADME properties. The presence of the diethylaminoethyl subunit in 18a– 18c led to enhanced antitrypanosomal potency, particularly for 18a and 18c, which contain unsubstituted and methoxy-substituted phenoxy moieties. They were found to be > 2-fold more potent against African trypanosomes than nifurtimox. Fluorescence and CD spectroscopy, thermal denaturation assays and computational analysis indicated a preference of 18a–18c toward AT-rich DNA and their minor groove binding mode. Replacement of the amidine group with less basic and ionisable nitrogen-containing moieties failed to improve membrane permeability of the investigated compounds. Due to structural diversification, the compounds displayed a range of physico-chemical features resulting in variable in vitro ADME properties, leaving space for further optimization of the biological profiles.

Izvorni jezik
Engleski

Znanstvena područja
Kemija

POVEZANOST RADA

Projekti:
HRZZ-IP-2018-01-4682 - Novi spojevi temeljeni na bioizosterima purina za ispitivanje njihovih antitumorskih i antipatogenih djelovanja (PurBioCaPa) (Raić-Malić, Silvana, HRZZ - 2018-01) ( CroRIS)
--IP-2018-01-4694 - Molekularno prepoznavanje DNA:RNA hibridnih i višelančanih struktura u bioanalitičkim i in vitro sustavima (DNARNAHyB-MolBio) (Radić Stojković, Marijana) ( CroRIS)

Ustanove:
Veterinarski fakultet, Zagreb,
Institut "Ruđer Bošković", Zagreb,
Fakultet kemijskog inženjerstva i tehnologije, Zagreb,
Fidelta d.o.o.

Profili:

Sanja Koštrun (autor)