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

## TL;DR

Researchers designed new drug candidates by combining two chemical fragments that target a key enzyme in parasites causing sleeping sickness and leishmaniasis.

## Contribution

A novel fragment hybridization approach was used to design 2-aminobenzothiazole derivatives with improved potency and reduced toxicity against trypanosomatid PTR1.

## Key findings

- Two compound series were created by combining 2-aminobenzothiazole and 3,4-dichlorophenyl moieties, showing potent inhibition of TbPTR1.
- Compound 1b was active against both TbPTR1 and LmPTR1, with moderate activity against Leishmania infantum.
- Meta-halogenation was found more favorable than para-halogenation for improved activity, though single halogenation reduced antiparasite effects.

## Abstract

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 I bind a different region of the Trypanosoma
brucei PTR1 (TbPTR1) pocket. This
study combines both moieties via various linkers, creating two compound
series screened in silico against TbPTR1 and Leishmania major PTR1 (LmPTR1).
In the first series, five compounds were synthesized, and 1a and 1b emerged as potent TbPTR1 inhibitors,
with 1b also being active against LmPTR1 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 I.