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

β-Pinene, a low-cost natural product derived from agricultural waste, has shown <i>in vitro</i> activity against <i>Leishmania amazonensis</i>, 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 <i>in vitro</i> evaluation of their antileishmanial activity, cytotoxicity profile in mammalian cells, and <i>in silico</i> 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 <i>para</i>-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, <i>in silico</i> ADMET supported their drug-likeness since no mutagenic, cardiotoxic, or hepatotoxic potential was predicted, encouraging further <i>in vivo</i> and mechanistic studies.