Τίτλος:
Structure-activity relationships in fungal nucleobases transporters as dissected by the inhibitory effects of novel purine analogues
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
We have previously rationally designed, synthesized and tested a number of 3-deazapurine analogues, which inhibit the ubiquitous fungal nucleobase transporter FcyB, through binding in its major substrate binding site, by specifically interacting with Asn163. Here, in an effort to further understand the molecular details of structure-activity relationships in all three major nucleobase transporters of fungi, we extend this study by designing, based on our previous experience, synthesizing and testing further 3-deazapurine analogues. We thus identify seven new compounds with relatively high affinity (19–106 μΜ) for the FcyB binding site. Importantly, four of these compounds can also efficiently inhibit AzgA, a structurally and evolutionary distinct, but functionally similar, purine transporter. Contrastingly, none of the new compounds tested had any effect on the transport activity of the uric acid-xanthine transporter UapA, albeit this being a structural homologue of AzgA. Besides the apparent importance for understanding how nucleobase transporter specificity is determined at the molecular level, our work might constitute a critical step in the design of novel purine-related antifungals. © 2018
Συγγραφείς:
Gavriil, E.-S.
Dimitrakis, S.
Papadaki, G.
Balaska, S.
Lambrinidis, G.
Lougiakis, N.
Marakos, P.
Diallinas, G.
Pouli, N.
Mikros, E.
Περιοδικό:
European Journal of Medicinal Chemistry
Εκδότης:
Elsevier Masson s.r.l.
Λέξεις-κλειδιά:
2 (2 hydroxyphenyl) 4 (4 methylpiperazin 1 yl) 1h imidazo[4,5 c]pyridine; 2 (2,5 dimethoxyphenyl) 4 (4 methylpiperazin 1 yl) 1h imidazo[4,5 c]pyridine; 3 benzyl 2 (2 hydroxyphenyl) 3h imidazo[4,5 b]pyridin 7 amine; 3 benzyl 2 (2,5 dimethoxyphenyl) 3h imidazo[4,5 b]pyridin 7 amine; 3 benzyl 2 (4 nitrophenyl) 3h imidazo[4,5 b]pyridin 7 amine; 3 benzyl 2 (pyridin 4 yl)imidazo[4,5 b]pyridin 7 amine; 3 deazapurine derivative; 4 (4 methylpiperazin 1 yl) 1,3 dihydroimidazo[4,5 c]pyridin 2 one; 4 (4 methylpiperazin 1 yl) 1,3 dihydroimidazo[4,5 c]pyridine 2 thione; 4 (4 methylpiperazin 1 yl) 2 (4 nitrophenyl) 1h imidazo[4,5 c]pyridine; 4 (4 methylpiperazin 1 yl) 2 (pyridin 4 yl) 1h imidazo[4,5c]pyridine; 4 benzylamino 1,3 dihydroimidazo[4,5 c]pyridin 2 one; 4 benzylamino 1,3 dihydroimidazo[4,5 c]pyridine 2 thione; 7 amino 3 benzyl 3h imidazo[4,5 b]pyridin 2 one; 7 amino 3 benzyl 3h imidazo[4,5 b]pyridine 2 thione; 8 azaguanine; n benzyl 2 (2 hydroxyphenyl) 1h imidazo[4,5 c]pyridin 4 amine; n benzyl 2 (2,5 dimethoxyphenyl) 1h imidazo[4,5 c]pyridin 4 amine; n benzyl 2 (4 nitrophenyl) 1h imidazo[4,5 c]pyridin 4 amine; n benzyl 2 (pyridin 4 yl) 1h imidazo[4,5 c]pyridin 4 amine; nucleobase transporter; nucleobase transporter FcyB; purine derivative; UapA protein; unclassified drug; 7-deazapurine; antifungal agent; fungal protein; nucleobase transporter; purine derivative, Article; binding affinity; controlled study; drug binding; drug binding site; drug design; drug identification; drug screening; drug synthesis; IC50; structure activity relation; antagonists and inhibitors; aspergillosis; Aspergillus nidulans; chemistry; drug design; drug effect; human; metabolism; microbiology; molecular docking; structure activity relation; transport at the cellular level, Antifungal Agents; Aspergillosis; Aspergillus nidulans; Biological Transport; Drug Design; Fungal Proteins; Humans; Molecular Docking Simulation; Nucleobase Transport Proteins; Purines; Structure-Activity Relationship
DOI:
10.1016/j.ejmech.2018.06.038
