title: Δ²,³-ivermectin ethyl secoester, a conjugated ivermectin derivative with leishmanicidal activity but without inhibitory effect on mammalian P-type ATPases.
abstract: Looking at a new putative target for the large spectrum antiparasitic drug ivermectin, we recently showed that avermectin-derived drugs are active against promastigote and amastigote forms of Leishmania amazonensis at low micromolar concentrations. However, we then reported that at this concentration range ivermectin is also able to inhibit three important mammalian P-type ATPases so that unacceptable adverse effects could occur if this drug were used at such high doses therapeutically. The present work aimed to test the activity of ten ivermectin analogs on these rat ATPases in search of a compound with similar leishmanicidal activity but with no effect on the mammalian (host) ATPases at effective concentrations. We synthesized three new ivermectin analogs for testing on rat SERCA (1a and 1b), Na+, K+-ATPase (α₁ and α₂/α₃ isoforms) and H+/K+-ATPase activity, along with seven analogs already characterized for their leishmanicidal activity. Our main finding is that one of the prepared derivatives, Δ²,³-ivermectin ethyl secoester 8, is equipotent to ivermectin 1 for the in vitro leishmanicidal effects but is nearly without effect on the rat ATPases, indicating that it could have a better therapeutic index in vivo and could serve as a candidate for hit-to-lead progression. This conclusion is further supported by the fact that compound 8 produced only 6% (vs 77% for ivermectin) inhibition of the human kidney enzyme at 5 μM, a concentration corresponding to the IC₅₀ for the activity against L. amazonensis amastigotes.
authors.affiliation: Laboratório de Farmacologia Bioquímica e Molecular, Instituto de Ciências Biomédicas, Centro de Ciências da Saúde, Bloco J-sala 17, Universidade Federal do Rio de Janeiro, Ilha do Fundão, Av. Carlos Chagas Filho 373, CEP: 21941-902, Rio de Janeiro, RJ, Brazil. fnoel@pharma.ufrj.br
authors.forename: François
authors.initials: F
authors.lastname: Noël
authors.forename: Paulo Henrique Cotrim
authors.initials: PH
authors.lastname: Pimenta
authors.forename: Anderson Rouge
authors.initials: AR
authors.lastname: Dos Santos
authors.forename: Erick Carlos Loureiro
authors.initials: EC
authors.lastname: Tomaz
authors.forename: Luis Eduardo Menezes
authors.initials: LE
authors.lastname: Quintas
authors.forename: Carlos Roland
authors.initials: CR
authors.lastname: Kaiser
authors.forename: Claudia Lucia Martins
authors.initials: CL
authors.lastname: Silva
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Férézou
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000825:Animal Structures / Q000201:enzymology; D000818:Animals; D055162:Biocatalysis / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017506:H(+)-K(+)-Exchanging ATPase / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D007559:Ivermectin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology*; D007668:Kidney / Q000201:enzymology; D007891:Leishmania / Q000187:drug effects*; D007894:Leishmania mexicana / Q000187:drug effects; D008297:Male; D015394:Molecular Structure; D054328:Proton Pump Inhibitors; D051381:Rats; D017208:Rats, Wistar; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000009:adverse effects / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D054328:Proton Pump Inhibitors; D014344:Trypanocidal Agents; D007559:Ivermectin; D000251:Adenosine Triphosphatases; D017506:H(+)-K(+)-Exchanging ATPase; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000254:Sodium-Potassium-Exchanging ATPase