Background/Objectives: In the Brazilian Amazon, which accounts for over 99% of national malaria cases, 34,260 cases were reported as of August 2025, predominantly caused by Plasmodium vivax, responsible for 86.69% of the infections. The increasing resistance of the parasite to conventional therapies highlights the urgent need for novel control strategies, with essential oils and plant-derived substances emerging as promising alternatives. Methods: In this context, we evaluated the anti-Plasmodium potential of Piper alatipetiolatum essential oil and its major constituent 6-ishwarone against P. vivax, including cytotoxicity in Vero and PBMCs, molecular docking on dihydrofolate reductase (DHFR) and lactate dehydrogenase (LDH), and in silico pharmacokinetic profiling. Results: Both the oil and 6-ishwarone inhibited P. vivax dose-dependently (2.1 ± 1 to 100%), with IC₅₀ values of 9.25 µg/mL and 3.93 µg/mL, respectively. Importantly, no cytotoxic effects were observed at 24 h, with cell viability ranging from 94.7% to 98.3%, highlighting the selectivity of these compounds towards the parasite over mammalian cells. Docking studies indicated selective binding of 6-ishwarone to DHFR (−7.7 kcal/mol; Ki = 2.27 µM) with key interactions (Trp816, Lys820, Tyr819, Asn823, Thr865), whereas binding to LDH was weaker (−6.2 kcal/mol; Ki = 28.10 µM), suggesting DHFR as the primary molecular target. In silico ADMET predictions and experimental data indicated favorable drug-like properties: TPSA = 20.23 Ų, moderate lipophilicity (LogP = 3.37), soluble (ESOL Log S = −3.58; Ali Log S = −3.89; Silicos-IT Log S = −2.84), high gastrointestinal absorption, BBB permeability (0.985), not a P-glycoprotein substrate (0.11), and low likelihood of CYP inhibition. Toxicity predictions showed non-mutagenic and non-hepatotoxic effects, low cardiotoxicity (hERG inhibition risk 0.08–0.32), low reproductive toxicity (0.03), moderate neurotoxicity (0.28), low acute toxicity (oral LD₅₀ = 2.061 mol/kg), and low chronic toxicity (LOAEL = 1.995 log mg/kg/day). Conclusions: Together, these findings demonstrate that essential oil and 6-ishwarone of P. alatipetiolatum are selective, bioavailable, and promising natural leads for antimalarial drug development.

Dengue, a mosquito‐borne disease transmitted mainly by Aedes aegypti , remains a major global public health concern. In the Americas, over 13 million cases were reported in 2024 and more than 4 million in 2025, highlighting the urgent need for effective preventive strategies. Repellents are among the most practical tools to reduce mosquito–human contact. In this study, the essential oil (EO) from Piper cyrtopodon and cadina‐1(10),4‐diene showed the highest repellent efficacy (EC ₅₀ = 2.68 and 2.31 mg/cm ² ), followed by germacrene D and δ‐Elemene (EC ₅₀ = 3.85 and 4.54 mg/cm ² ). All treatments maintained high repellency levels for up to 270 min under laboratory conditions, showing performance comparable to the reference compound DEET within the experimental conditions. Molecular docking with the mosquito odorant‐binding proteins OBP1 and OBP22 suggested favorable binding interactions with the major compounds (–6.8 to –8.4 kcal/mol for OBP1 and –6.8 to –7.3 kcal/mol for OBP22), involving hydrophobic and aromatic contacts within the binding cavity. ADMET predictions indicated high lipophilicity, low aqueous solubility, and limited systemic absorption. No significant cytotoxicity was observed in Vero and PBMC cells up to 25 µg/mL for 72 h. These findings highlight the EO from P. cyrtopodon as a potential source of natural compounds with repellent activity, with emphasis on behavioral repellency under controlled laboratory conditions.