Biological Sciences Evaluation of Antileishmanial Activities of Lactam Fused Tetrahydropyrans and Lactam Fused Halolactones Against Leishmania major , the Causative Agent of Human Cutaneous Leishmaniasis Francis Aminkiah* Project Mentor(s): Blaise Dondji, PhD; Timothy Beng, PhD Leishmaniasis is a neglected tropical disease, causing 70,000 deaths annually with 1.2 million new infections. Transmitted by female phlebotomine sand flies, it presents in three forms; cutaneous, mucocutaneous and visceral –with Leishmania major driving the cutaneous form. Current treatments like Amphotericin B, Miltefosine, and Paromomycin are limited by toxicity, resistance, and high costs, highlighting the urgent need for new therapies. While bicyclic heterocycles are established in anticancer, antibiotics, and anticoagulant drugs, their application against Leishmania remains largely underexplored. This study evaluates two fused bicyclic scaffolds –lactam tetrahydropyrans and lactam halolactones as potential antileishmanial agents. Both were screened against Leishmania major promastigotes using an Alamar Blue colorimetric assay. Among 17 lactam tetrahydropyrans, IC 50 values ranged from 31.53 to 84.68 µM, with compound 3a (IC 50 = 31.53 µM) being the most active, attributed to its brominated stereocenter and methyl group. The 21 halolactones derivatives showed IC 50 values of 27.9 µM to 71.6 µM, with compound 2k (IC 50 = 27.9 µM) the most active, benefitting from CF 3 group and otho- methoxy substitution. Structure activity relationship (SAR) analysis further confirms the importance of methyl substituents on these bicyclic compounds, which is consistent with the well-documented magic methyl effect in medicinal chemistry. Selectivity assessment against MCF-10A cells revealed modest parasite selectivity for several halolactones derivatives (SI ≈ 2-3), indicating partial therapeutic windows with limited mammalian toxicity. While potency remains at the moderate activity range, both scaffolds show chemical novelty and clear SAR tractability, making them promising candidates for further optimization and in vivo evaluation. Presentation Type: Oral Presentation (May 20, 9:30am–5:00pm) Keywords: Leishmania major , Lactam tetrahydropyrans, Lactam halolactones, Structure activity relationship, Selectivity assessment SOURCE Form ID: 246
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