# Hit-Identification to Novel Antileishmanial Agents from a β‑Pinene Scaffold: from Synthesis to In Vitro Evaluation and In Silico SAR/ADMET Profiling

## TL;DR

Researchers developed new antileishmanial compounds from β-pinene, a natural product, and identified a promising hit with good activity and safety profiles.

## Contribution

A novel β-pinene-derived compound with strong antileishmanial activity and favorable ADMET properties was identified.

## Key findings

- Eleven compounds reduced Leishmania viability to <10% at 100 μM.
- A para-fluoroaryl derivative showed an IC50 of 6.3 μM against intracellular amastigotes.
- In silico ADMET analysis showed no mutagenic, cardiotoxic, or hepatotoxic potential.

## Abstract

β-Pinene, a low-cost natural product derived from
agricultural
waste, has shown in vitro activity against Leishmania amazonensis, but its use is hindered by
unfavorable pharmacokinetic properties. Herein, we report a straightforward
two-step synthesis of β-pinene-derived hydroxysulfides followed
by an in vitro evaluation of their antileishmanial
activity, cytotoxicity profile in mammalian cells, and in
silico studies of structure–activity relationship
(SAR) and ADMET properties. Initially, β-pinene was converted
into its epoxide, the key intermediate of the series, through both
chemoenzymatic and nonchemoenzymatic approaches. Then, we studied
the thiolysis reaction by screening a series of bases and solvents.
The use of NaOMe in methanol afforded the β-hydroxysulfide in
81% yield. This strategy afforded 16 novel derivatives bearing alkyl
and (hetero)­aryl substituents, with isolated yields ranging from 19
to 91%. The antileishmanial activity with promastigote cells showed
that 11 compounds reduced parasite viability to <10% in a fixed-concentration
assay (100 μM), and six displayed IC50 values below
30 μM. Four derivatives were further evaluated against intracellular
amastigote cells, with the para-fluoroaryl analogue
emerging as a hit compound (IC50 = 6.3 μM; SI >
15.9).
SAR analysis revealed key physicochemical features associated with
activity, highlighting the importance of lipophilicity, polar surface
area, and cLogP in promoting parasite membrane penetration. Meanwhile, in silico ADMET supported their drug-likeness since no mutagenic,
cardiotoxic, or hepatotoxic potential was predicted, encouraging further in vivo and mechanistic studies.