@article{fdi:010084410,
  title = {{P}otent antiplasmodial derivatives of dextromethorphan reveal the ent-morphinan pharmacophore of tazopsine-type alkaloids},
  author = {{K}eita, {A}. and {F}ranetich, {J}. {F}. and {C}arraz, {M}a{\¨e}lle and {V}alentin, {L}. and {B}ordessoules, {M}. and {B}aron, {L}. and {B}igeard, {P}. and {D}upuy, {F}. and {G}eay, {V}. and {T}efit, {M}. and {S}arrasin, {V}. and {M}ichel, {S}. and {L}avazec, {C}. and {H}ouze, {S}. and {M}azier, {D}. and {S}oulard, {V}. and {P}oree, {F}. {H}. and {D}uval, {R}omain},
  editor = {},
  language = {{ENG}},
  abstract = {{T}he alkaloid tazopsine 1 was introduced in the late 2000s as a novel antiplasmodial hit compound active against {P}lasmodium falciparum hepatic stages, with the potential to develop prophylactic drugs based on this novel chemical scaffold. {H}owever, the structural determinants of tazopsine 1 bioactivity, together with the exact definition of the pharmacophore, remained elusive, impeding further development. {W}e found that the antitussive drug dextromethorphan ({DXM}) 3, although lacking the complex pattern of stereospecific functionalization of the natural hit, was harboring significant antiplasmodial activity in vitro despite suboptimal prophylactic activity in a murine model of malaria, precluding its direct repurposing against the disease. {T}he targeted {N}-alkylation of nor-{DXM} 15 produced a small library of analogues with greatly improved activity over {DXM} 3 against {P}. falciparum asexual stages. {A}mongst these, {N}-2 '-pyrrolylmethyl-nor-{DXM} 16i showed a 2- to 36-fold superior inhibitory potency compared to tazopsine 1 and {DXM} 3 against {P}. falciparum liver and blood stages, with respectively 760 +/- 130 n{M} and 2.1 +/- 0.4 mu {M} {IC}50 values, as well as liver/blood phase selectivity of 2.8. {F}urthermore, cpd. 16i showed a 5- to 8-fold increase in activity relative to {DXM} 3 against {P}. falciparum stages {I}-{II} and {V} gametocytes, with 18.5 mu {M} and 13.2 mu {M} {IC}50 values, respectively. {C}pd. 16i can thus be considered a promising novel hit compound against malaria in the ent-morphinan series with putative pan cycle activity, paving the way for further therapeutic development (e.g., investigation of its prophylactic activity in vivo).},
  keywords = {malaria ; {P}lasmodium berghei ; {P}lasmodium falciparum ; hepatic stages ; blood stages ; prophylaxis ; tazopsine ; dextromethorphan ; {N}-alkylation ; hit compound},
  booktitle = {},
  journal = {{P}harmaceutics},
  volume = {14},
  numero = {2},
  pages = {372 [23 ]},
  year = {2022},
  DOI = {10.3390/pharmaceutics14020372},
  URL = {https://www.documentation.ird.fr/hor/fdi:010084410},
}