Design of 2‑Aminobenzothiazole Derivatives Targeting Trypanosomatid PTR1 by a Multidisciplinary Fragment Hybridization Approach

Pteridine reductase 1 (PTR1) is a folate pathway enzyme essential for pathogenic trypanosomatids and a promising drug target for diseases such as sleeping sickness and leishmaniasis. Previous studies have shown that the 2-aminobenzothiazole moiety targets the PTR1 biopterin pocket, while 3,4-dichlorophenyl-containing compounds, such as <b>I</b> bind a different region of the Trypanosoma brucei PTR1 (<i>Tb</i>PTR1) pocket. This study combines both moieties via various linkers, creating two compound series screened in silico against <i>Tb</i>PTR1 and Leishmania major PTR1 (<i>Lm</i>PTR1). In the first series, five compounds were synthesized, and <b>1a</b> and <b>1b</b> emerged as potent <i>Tb</i>PTR1 inhibitors, with <b>1b</b> also being active against <i>Lm</i>PTR1 and moderately effective against Leishmania infantum. Furthermore, structure–activity relationship analysis, supported by quantum calculations and crystallography, revealed meta-halogenation to be more favorable than para, although single halogenation reduced antiparasite effects. Our fragment hybridization approach led to less toxic, more effective compounds than <b>I</b>.