The Nitrobenzoxadiazole Derivative NBDHEX Behaves as Plasmodium falciparum Gametocyte Selective Inhibitor with Malaria Parasite Transmission Blocking Activity.

Giulia Siciliano,Marco Lalle,Serena Camerini,Anna Maria Caccuri,Rossella Migale,Dante Rotili,Pietro Alano,Luigi Quintieri,Antonello Mai,Daniele Dalzoppo,Marialuisa Casella,Veronica Di Paolo,Francesca Pedini,Tonnie Huijs,Koen J Dechering,Rob Henderson

doi:10.3390/ph15020168

Abstract

This work describes the activity of 6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)hexan-1-ol (NBDHEX) and of its newly identified carboxylic acid metabolite on the human malaria parasite Plasmodium falciparum. NBDHEX has been previously identified as a potent cytotoxic agent against murine and human cancer cells as well as towards the protozoan parasite Giardia duodenalis. We show here that NBDHEX is active in vitro against all blood stages of P. falciparum, with the rare feature of killing the parasite stages transmissible to mosquitoes, the gametocytes, with a 4-fold higher potency than that on the pathogenic asexual stages. This activity importantly translates into blocking parasite transmission through the Anopheles vector in mosquito experimental infections. A mass spectrometry analysis identified covalent NBDHEX modifications in specific cysteine residues of five gametocyte proteins, possibly associated with its antiparasitic effect. The carboxylic acid metabolite of NBDHEX retains the gametocyte preferential inhibitory activity of the parent compound, making this novel P. falciparum transmission-blocking chemotype at least as a new tool to uncover biological processes targetable by gametocyte selective drugs. Both NBDHEX and its carboxylic acid metabolite show very limited in vitro cytotoxicity on VERO cells. This result and previous evidence that NBDHEX shows an excellent in vivo safety profile in mice and is orally active against human cancer xenografts make these molecules potential starting points to develop new P. falciparum transmission-blocking agents, enriching the repertoire of drugs needed to eliminate malaria.

Highlights

IntroductionP1-1 (GSTP1-1) for cancer therapy led to the discovery of 6-((7-nitrobenzo[c][1,2,5]oxadiazol4-yl)thio)hexan-1-ol (NBDHEX, 1, Figure 1)
A search for non-GSH-peptidomimetic inhibitors of human glutathione S-transferaseP1-1 (GSTP1-1) for cancer therapy led to the discovery of 6-((7-nitrobenzo[c][1,2,5]oxadiazol4-yl)thio)hexan-1-ol (NBDHEX, 1, Figure 1)
As 1 is active on human tumor cells by inhibiting glutathione S-transferaseP1-1 (GSTP1-1), this may suggest that GST

Summary

Introduction

P1-1 (GSTP1-1) for cancer therapy led to the discovery of 6-((7-nitrobenzo[c][1,2,5]oxadiazol4-yl)thio)hexan-1-ol (NBDHEX, 1, Figure 1) This nitrobenzoxadiazole (NBD) derivative is Pharmaceuticals 2022, 15, 168. This nitrobenzoxadiazole (NBD) derivative is amechanism-based potent mechanism-based of bothGSTP1-1 human GSTP1-1 and GSTM2-2 and a potent inhibitorinhibitor of both human and GSTM2-2 and exhibits values in exhibits remarkable cytotoxicity towards various cultured cancer cell lines (IC remarkable cytotoxicity towards various cultured cancer cell lines (IC50 values in the the low micromolar/submicromolar range) [1]. NBDHEX has inin mouse models andand is orally active in mice bearNBDHEX has an anexcellent excellentsafety safetyprofile profile mouse models is orally active in mice ing human cancer xenografts [2,3]; [2,3];

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