Antitrypanosomal 8-Hydroxy-Naphthyridines Are Chelators of Divalent Transition Metals

Abstract

The lack of information regarding the mechanisms of action (MoA) or specific molecular targets of phenotypically active compounds can prove a barrier to their development as chemotherapeutic agents. Here, we report the results of our orthogonal genetic, molecular, and biochemical studies to determine the MoA of a novel 7-substituted 8-hydroxy-1,6-naphthyridine (8-HNT) series that displays promising activity against Trypanosoma brucei and Leishmania donovani.

Host-Directed Drug Therapies for Neglected Tropical Diseases Caused by Protozoan Parasites

“…Chelating compounds have myriad positive effects for the host including anti-inflammatory and antioxidant properties. 1,8-naphthyridine derivative compounds are particularly of interest, as they have been shown to possess anti-trypanosomal activity via their ability to chelate Zn 2+ , Cu 2+ and Fe 2+ which are necessary for trypanosomes to thrive in the host ( Wall et al, 2018 ). Thiosemicarbazone has also shown to have some efficacy in ridding a host of trypanosomes through chelation of iron ( Ellis et al, 2015 ).…”

Pyrazolyl-pyrimidones inhibit the function of human solute carrier protein SLC11A2 (hDMT1) by metal chelation

“… 35 However, the screens performed were not transport assays but simple cytotoxicity tests. Considering that metal chelation is known to be a mechanism of toxicity against these parasites, 36 , 37 one can speculate that the reported transporter inhibitory activity of these pyrazolyl-pyrimidones might in fact reflect toxicity as a result of metal chelation. Further activities reported for pyrazolyl-pyrimidones and pyrazolyl-pyridines might similarly be the consequence of metal chelation rather than the attributed activity, including a recently reported activity of 3 and 5 against cancer cells.…”

Live-imaging rate-of-kill compound profiling for Chagas disease drug discovery with a new automated high-content assay

“…Posaconazole was purchased from Sequoia Research Products. All other compounds were synthesised in house as previously published [12][13][14][15][16][17].…”

“…To explore the diversity of RoK profiles in compounds from our Chagas drug discovery programmes we tested a set of previously published new chemical entities (NCEs) in the liveimaging assay (Figs S2 and 3A), including 2,4-diamino-6-methylpyrimidines [14] and 5-amino-1,2,3-triazole-4-carboxamides [12] with unknown mode-of-action (referred to as TCAMS06 and ES08 respectively), divalent transition metal chelating 8-hydroxy-naphthyridines (referred to as B series) [15], 2-amino benzimidazole and aminoquinazolinone inhibitors of T. cruzi methionyl tRNA-synthetase (MetRS) [13], chromone inhibitors of T. cruzi lysyl tRNA-synthetase (LysRS) [22], and the oxaborole SCYX-6759, which in the related organism Trypanosoma brucei acts through inhibition of the nuclear mRNA processing endonuclease, cleavage and polyadenylation specificity factor 3 [16,23,24]. All compounds were tested at four concentrations above their EC 50 (as generated in our routine screening assay [9]) (S2 Fig) , and the fastest RoK profile is presented on Fig 3 . We observed clear differences in profiles, with differences in lag phase and kill rate.…”