2026-10-12T04:49:52Z https://api.figshare.com/v2/oai

oai:figshare.com:article/34038012 2026-10-01T04:04:45Z category_4 category_915 category_7 category_12 category_19 category_21 category_272 category_873 category_734 category_132 portal_63 item_type_6 month_year_10_2026

4‑O‑Allyl Derivative of Natural Licarin A Exhibits Selective In Vitro Activity against Toxoplasma gondii Tachyzoites Gabriel Candido Moura (25151508) Stephanie Ortega Alves (25151511) Ingrid de Oliveira Dias (25151514) João Paulo dos Santos Fernandes (19816245) Daniela da Costa Tristão (25151517) João Henrique Ghilardi Lago (17703908) Juliana Quero Reimão (22005182) Biochemistry Physical Sciences not elsewhere classified Medicine Cell Biology Pharmacology Biotechnology Environmental Sciences not elsewhere classified Chemical Sciences not elsewhere classified Biological Sciences not elsewhere classified Infectious Diseases widespread parasitic disease serious health threat provide additional evidence new antitoxoplasmic agents mechanistic assays demonstrated functional analyses revealed eliminate latent infections highest selectivity index >- allyl derivative licarin scaffold represents 4 ‑< italic three semisynthetic derivatives highest concentration tested 1c </ b vitro </ italic 50 </ sub highest potency tested compounds semisynthetic modification 4 -< vitro activity silico </ gondii </ resazurin assay promising strategy present study pregnant women intracellular mode immunocompromised patients findings identify exhibits selective drug removal determined using dependent manner based assay adverse effects 49 μm 41 ). (< b Toxoplasma gondii is an obligate intracellular protozoan responsible for toxoplasmosis, a widespread parasitic disease that poses a serious health threat, especially to immunocompromised patients and pregnant women. Current therapeutic options remain unsatisfactory because they are associated with adverse effects and do not eliminate latent infections, emphasizing the need for new antitoxoplasmic agents. In the present study, the natural neolignan (−)-licarin A (1), isolated from the Brazilian species Nectandra oppositifolia, together with three semisynthetic derivatives, 4-O-methyl (1a), 4-O-acetyl (1b), and 4-O-allyl (1c), were investigated for their in vitro activity against T. gondii tachyzoites. Antiparasitic activity (EC50) was determined using a β-galactosidase-based assay, while cytotoxicity (CC50) toward Human Foreskin Fibroblasts (HFF) was assessed by the resazurin assay. Among the tested compounds, derivative 1c exhibited the highest potency (EC50 = 3.49 μM) and lowest cytotoxicity (CC50 = 120.10 μM), resulting in the highest selectivity index (SI = 34.41). In silico ADMET analysis predicted favorable gastrointestinal absorption and blood–brain barrier permeability for all licarin derivatives. Mechanistic assays demonstrated that licarin A derivatives 1a–1c did not compromise parasite plasma membrane integrity but significantly reduced mitochondrial membrane potential, supporting an intracellular mode of action. Further functional analyses revealed that compound 1c inhibited intracellular parasite proliferation in a concentration-dependent manner and maintained significant antiparasitic activity after drug removal only at the highest concentration tested, without affecting parasite invasion or intracellular replication following pretreatment of extracellular tachyzoites. Overall, these findings identify the 4-O-allyl derivative of licarin A as the most selective compound of this series and provide additional evidence that semisynthetic modification of the licarin scaffold represents a promising strategy for discovering new therapeutic candidates against T. gondii. 2026-10-01T00:00:00Z Text Journal contribution 10.1021/acsomega.6c05944.s001 https://figshare.com/articles/journal_contribution/4_O_Allyl_Derivative_of_Natural_Licarin_A_Exhibits_Selective_In_Vitro_Activity_against_Toxoplasma_gondii_Tachyzoites/34038012 CC BY-NC 4.0