Document Type
Thesis
Date of Degree Completion
Spring 2026
Degree Name
Master of Science (MS)
Department
Biology
Committee Chair
Dr. Blaise Dondji
Second Committee Member
Dr. Timothy Beng
Third Committee Member
Dr. Gabrielle Stryker
Abstract
The leishmaniases are a group of vector-borne disease caused by the protozoan parasite Leishmania with the female phlebotomine sand fly being the vector. The disease poses a severe public health challenge with 1.2 million new cases and about 70,000 deaths recorded annually. This protozoan infection manifests clinically in three distinct ways, presenting as cutaneous, mucocutaneous or visceral forms. Leishmania major serves as the primary agent of cutaneous leishmaniasis, which results in disfiguring skin lesions. Existing treatments, including Amphotericin B, Miltefosine and Paromomycin pose toxicity, parasite resistance and prohibitive cost challenges. Therefore, there is a dire need for novel, safer and cost-effective antileishmanial therapies. This study explores the therapeutic potential of lactam-fused halolactones and lactam-fused tetrahydropyrans scaffolds. While bicyclic heterocycles are established in anticancer, antibiotic and anticoagulant drugs, their application against Leishmania remains largely underexplored. To contribute to this goal, synthesized lactams-fused halolactones and lactam-fused tetrahydropyrans were screened for activity against Leishmania major promastigotes. A colorimetric Alamar Blue assay was used to assess parasite viability in the presence of the compounds. Structure-Activity Relationship analysis revealed that 21 lactam-fused halolactones and 17 lactam-fused tetrahydropyrans exhibited mid micromolar activities ranging from 27.9 to 71.6 µM and 31.5 to 84.7 µM respectively. Compound 2k (IC50=27.9 µM) which was the most active among the halolactones enjoys the combined effects of the trifluoromethyl and ortho methoxy substitutions. On the other hand, compound 11b (IC50=31.5 µM) which emerged as the most active tetrahydropyrans has a tetrasubstituted stereocenter bearing bromine and methyl substituents. Cytotoxicity assessment of the two compound classes showed moderate toxicity in mammalian cell lines. Overall, compound 2k emerged as the most promising with selectivity index of 3. Although potency of these two compound classes remain within the early stage hit-identification range, the chemical novelty, tractable structure-activity relationship and favorable predicted drug-like properties support these bicyclic compounds as excellent starting points for further optimization in antileishmanial drug discovery.
Recommended Citation
Aminkiah, Francis, "Evaluation of Antileishmanial Activities of Lactam-fused Halolactones and Lactam-fused Tetrahydropyrans Against Leishmania major, the Causative Agent of Human Cutaneous Leishmaniasis" (2026). All Master's Theses. 2339.
https://digitalcommons.cwu.edu/etd/2339