https://tigerprints.clemson.edu/csrp/1002/thumbnail.jp

Kwain, Samuel

Morris, James W. D.

Whitehead, Daniel C.

English

Clemson University: TigerPrints

Clemson University TigerPrints Chemistry Summer Research Program Student Works 7-2023 Accessing Rare Heterocycles from Alkynyl Ethers and Nitrogenous Electrophiles & The Development of Small Molecule Inhibitors Against Naegleria fowleri infection James W. D. Morris Samuel Kwain Daniel C. Whitehead Follow this and additional works at: https://tigerprints.clemson.edu/csrp  Part of the Chemistry Commons James W.D. Morris1, Samuel Kwain2, Daniel C. Whitehead2*1Western Carolina University, Cullowhee NC & 2Department of Chemistry, Clemson University, Clemson SCBackgroundq Trypanosoma brucei is responsible for causing “sleeping sickness” (African Trypanosomiasis) in humans q Sleeping sickness is fatal if left untreated. q Diazocyclobutenes (DCB, 3) exhibit potent antitrypanisomal activity.q The present study investigates DCBs using alkynyl ethers instead of alkynyl sulfides or ynamines.Project Aimsq Access DCB from phenyltriazolinedione (PTAD, 2) and alkynyl ethers q Access Beta-Lactam from DCB via hydrolysisAccessing Alkynyl Ethers Accessing DCBCatalyst induced cyclization Accessing Beta-LactamComplete Alkynyl Ether Substrate ScopeComplete Beta-Lactam Substrate Scopeq Substrate scope investigated so far, however, this would be expanded to include other functional groups in hopes of uncovering more effective molecules. Complete DCB Substrate ScopeAccessing Rare Heterocycles from Alkynyl Ethers and Nitrogenous ElectrophilesThe Development of Small Molecule Inhibitors Against Naegleria fowleri infection&q Naegleria fowleri is an amoeba commonly found in warm freshwater (lakes, rivers, and hot springs) and poorly treated water sources.q Infection in humans is established when trophozoites from contaminated water enter the nose and travel into the brain. q Once infection is established, Naegleria folweri is >95% lethal. only 5 people have survived infection in North America. IntroductionProject AimSynthesis Schemes for compounds 2, 3 and 5 ConclusionSynthesized molecules will be investigated for their antitrypanosomal activityq N. fowleri harbors a single enolase gene (NfENO) that plays a crucial role during glycolysis for the survival of the amoebaq Our previous study revealed that the human ENO2 phosphonate inhibitor (HEX) is a potent inhibitor of  NfENO and is also toxic to the amoebae.q The current study explores the structure-activity relationship (SAR) of the HEX scaffold to design new compounds (1-5) guided by favorable binding interactions with the NfENO active site through molecular modeling NfENO-HEX complex  Binding affinity (-8.9 kcal/mol)nfENO IC50 (µM)0.14 ± 0.04N. Fowleri EC50 (µM)0.21±0.02NfENO(PDB 7UGH)Na+Na+Na+Na+Na+Na+Na+Na+New compoundsNfENO-2 complex  (-7.7 kcal/mol)NfENO-3 complex  (-6.4 kcal/mol)NfENO-4 complex  (-6.2 kcal/mol)NfENO-5 complex  (-7.2 kcal/mol)NfENO-1b complex       (-6.7 kcal/mol)NfENO-1c complex  (-7.7 kcal/mol)NfENO-1d complex  (-7.1 kcal/mol)NfENO-1a complex       (-7.0 kcal/mol)Conclusion AcknowledgmentsNSF REU Grant CHE #2050042Department of Chemistry, Clemson UniversityDepartment of Genetics and Biochemistry, Clemson UniversityThermally induced cyclization qSmall molecule competitive inhibition against NfENO might impede glucosemetabolism in the N. fowleri lifecycle stage.qThe NfENO inhibitors may prove useful for future therapy for N. fowleri infections, alone or in concert with other agents. 

Accessing Rare Heterocycles from Alkynyl Ethers and Nitrogenous Electrophiles & The Development of Small Molecule Inhibitors Against Naegleria \u3ci\u3efowleri\u3c/i\u3e infection

https://tigerprints.clemson.edu/context/csrp/article/1002/viewcontent/REU_Morris_POSTER.pdf

Accessing Rare Heterocycles from Alkynyl Ethers and Nitrogenous Electrophiles & The Development of Small Molecule Inhibitors Against Naegleria \u3ci\u3efowleri\u3c/i\u3e infection

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