Chroman-4-One Derivatives Targeting Pteridine Reductase 1 and Showing Anti-Parasitic Activity

Abstract

Flavonoids have previously been identified as antiparasitic agents and pteridine reductase 1 (PTR1) inhibitors. Herein, we focus our attention on the chroman-4-one scaffold. Three chroman-4-one analogues (1–3) of previously published chromen-4-one derivatives were synthesized and biologically evaluated against parasitic enzymes (Trypanosoma brucei PTR1–TbPTR1 and Leishmania major–LmPTR1) and parasites (Trypanosoma brucei and Leishmania infantum). A crystal structure of TbPTR1 in complex with compound 1 and the first crystal structures of LmPTR1-flavanone complexes (compounds 1 and 3) were solved. The inhibitory activity of the chroman-4-one and chromen-4-one derivatives was explained by comparison of observed and predicted binding modes of the compounds. Compound 1 showed activity both against the targeted enzymes and the parasites with a selectivity index greater than 7 and a low toxicity. Our results provide a basis for further scaffold optimization and structure-based drug design aimed at the identification of potent anti-trypanosomatidic compounds targeting multiple PTR1 variants.

Protein model built through molecular modeling by homology of a potential target of anti-leishmania drugs

“…Inhibitors of Pteridine Reductase 1 (PTR1) proved to be lethal to the parasites in Leishmania spp. and Trypanosoma brucei, but not in human cells [4].…”

“…Previous studies have reported as the PTR1 as an important target chemotherapeutic [3,4]. Inhibitors of Pteridine Reductase 1 (PTR1) proved to be lethal to the parasites in Leishmania spp.…”

High-resolution crystal structure of Trypanosoma brucei pteridine reductase 1 in complex with an innovative tricyclic-based inhibitor

“…Crystallization was performed by the hanging-drop vapordiffusion technique at room temperature (Benvenuti & Mangani, 2007). Well ordered monoclinic crystals of histidinetagged TbPTR1 grew within a few days (to final dimensions of $600 Â 200 Â 50 mm) using a precipitant solution composed of 2-2.5 M sodium acetate, 0.1 M sodium citrate pH 5, as described elsewhere (Di Pisa et al, 2017). A dimethylsulfoxide (DMSO) solution of the compound was added to the cryoprotectant [composed of the precipitant enriched to 30%(v/v) glycerol] to a final concentration of 4 mM [the DMSO concentration was kept lower than 10%(v/v)].…”

“…The TbPTR1 inhibitors developed to date were conceived as substrate-competitive inhibitors and are based on a wide variety of scaffolds, including 2,4-diaminopteridine (Dawson et al, 2006;Tulloch et al, 2010), quinazoline (Dawson et al, 2010), 2,4-diaminopyrrolopyrimidine (Tulloch et al, 2010), chromone (Borsari et al, 2016;Di Pisa et al, 2017), 2-aminothiadiazole (Linciano et al, 2017), 2-aminobenzimidazole (Mpamhanga et al, 2009), triazine (Tulloch et al, 2010), 1,6-dihydrotriazine (Landi et al, 2019) and 2-aminobenzothiazole (Linciano et al, 2019). More than 60 crystal structures of TbPTR1-inhibitor complexes have now been deposited in the Protein Data Bank (PDB), clarifying the key binding interactions that occur inside the catalytic cavity (Pozzi et al, 2018).…”

The genus Calea L.: A review of isolated compounds and biological activities

“…Some chroman and chromene derivatives have exhibited DNA gyrase inhibition, and within the chromanones, a hydrogen bond donor/acceptor functionality at the 4-position together with a lipophilic 2-alkyl moiety is believed to be important for antibacterial activity. Much interest has focused on the use of chromenes as antiparasitic agents, with chromen/chroman-4-ones suggested to exert their effects through pteridine reductase 1 (PTR1) inhibition within both Trypanosoma brucei and Leishmania species (Di Pisa et al, 2017).…”