Synthesis, Anti‐ Leishmania amazonensis Activity, Cytotoxicity, and Molecular Docking of Anthranilate–Naphthoquinone Hybrids
Eduardo Miranda da Silva Magesfeste, Lidilhone Hamerski, Diego Mendes Nunes, Ana Paula Sotero da Silva Ribeiro, Elvira Maria Saraiva, Magaly Girão Albuquerque, Camilo Henrique da Silva Lima, Bárbara Vasconcellos da SilvaABSTRACT
Neglected tropical diseases affect over one billion people globally, with leishmaniasis remaining a major health challenge. This study describes the synthesis and in vitro biological evaluation of ten novel anthranilate–naphthoquinone hybrids as potential anti‐ Leishmania amazonensis agents. Isatoic anhydrides were synthesized from substituted isatins and subsequently coupled with aminonaphthoquinones via ethyl and propyl spacers, yielding compounds in 61%–98%. All were screened in vitro against promastigote forms, with iodinated/brominated derivatives with ethyl/propyl spacers showing the most promising activity profiles. Moreover, moderate in vitro potency against intracellular amastigotes infecting murine (mouse) macrophages was observed for 2‐((1,4‐naphthoquinyl)amino)ethyl‐2‐amino‐5‐bromobenzoate (IC 50 = 30.5 µM) and its propyl analogue (IC 50 = 31 µM). Both compounds exhibited low cytotoxicity (CC 50 > 250 µM), supporting a favorable selectivity profile (selectivity index, SI > 8.00). Although miltefosine, the reference oral anti‐ Leishmania drug, is still more potent in vitro and has a higher selectivity index (SI > 17.6), its clinical toxicity and resistence highlights the need for safer alternatives. Consensus docking of these two compounds pointed trypanothione reductase, leishmanolysin (or glycoprotein 63, GP63), and pteridine reductase from L. amazonensis as potential target enzymes. These findings highlight brominated anthranilate–naphthoquinones as promising structures for further optimization toward the development of new anti‐ Leishmania agents.