Structure-activity relationships in fungal nucleobases transporters as dissected by the inhibitory effects of novel purine analogues

Eur J Med Chem. 2018 Aug 5;156:240-251. doi: 10.1016/j.ejmech.2018.06.038. Epub 2018 Jun 18.

Abstract

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.

Keywords: Aspergillus nidulans; Imidazo[4,5-c]pyridine; Molecular dynamics; Purine isosters; Purine transporters; Rational design.

MeSH terms

  • Antifungal Agents / chemistry
  • Antifungal Agents / pharmacology
  • Aspergillosis / drug therapy
  • Aspergillosis / microbiology
  • Aspergillus nidulans / drug effects
  • Aspergillus nidulans / metabolism*
  • Biological Transport / drug effects
  • Drug Design*
  • Fungal Proteins / antagonists & inhibitors*
  • Fungal Proteins / metabolism
  • Humans
  • Molecular Docking Simulation
  • Nucleobase Transport Proteins / antagonists & inhibitors*
  • Nucleobase Transport Proteins / metabolism
  • Purines / chemistry*
  • Purines / pharmacology*
  • Structure-Activity Relationship

Substances

  • 7-deazapurine
  • Antifungal Agents
  • Fungal Proteins
  • Nucleobase Transport Proteins
  • Purines