Synthesis of Chalcones: Starting Materials for the Synthesis Of Parasite-targeted Compounds

Sarah Canch é Lee Lab Group

Malaria, Leishmaniasis, and Trypanosomiasis

 Diseases caused by protozoan parasites transmitted by mosquitoes, sand flies, and tsetse flies

Some Symptoms

Malaria:  Dry cough, fever, headache, fatigue, body aches Leishmaniasis:  Skin sores, fever, visceral swelling Trypanosomiasis:  Muscle and joint aches, fever, confusion, slurred speech

Widespread Problem:

 Malaria: 1-3 million deaths per year  Trypanosomiasis: 50,000 to 70,000 cases per year     Leishmaniasis: 10-15 million have it, with 1.5 to 2 million new cases per year Treatment for these diseases is expensive and not always effective Parasites can develop resistance Need to make treatments that are more affordable and effective

Pentamidine and Furamidine

O  Molecule currently being used to fight parasitic diseases  Destroys parasite DNA   Molecule that has been proven to help fight parasitic diseases. Goal: Make a molecule similar to this   Increase potency Cheaper to produce + H 2 N N NH NH 2 H 2 N + NH 2 O Pentamidine H 2 N + NH 2 O Furamidine NH 2 + NH 2 + NH 2 + H 2 N NH 2 NH 2 S HN NH NH 2 + NH 2 + NH 2 NH 2

Synthetic Pathways

Diarylpyrazolediamidine Synthesis

R O CH 3 R' O H 15 M NaOH 95% Ethanol R O R' K 2 CO 3 35% H 2 O 2 CH 3 OH O O R' R N NH H 2 N + H 2 N NH 2 + NH 2

Thioxopyrimidine Synthesis O

1. Acetyl Chloride dry MeOH 2. NH 3 dry MeOH, 0*C R

R R' Thiourea K 2 CO 3 EtOH Reflux R

N NH R, R'=CN

S HN NH

R'

R'

Hydrazine Hydrate p-Toluenesulfonic Acid Xylenes Reflux

How to synthesize chalcones: Method 1

O R O CH 3 R' O H 15 M NaOH 95% Ethanol R R' To make… O NC O H 3 CO OCH 3 86% yield CN 94% yield

Method 2

O CH 3 + R R O H 1 M NaOH MeOH Reflux NC O CN 65% yield 6 M NaOH MeOH Reflux O H 3 CO OCH 3 94% yield •Methanol added to flask •Reaction mixture heated to reflux •1 M NaOH added to the mixture •Solid forms •Solid collected by vacuum filtration

What I learned

     Run an NMR Run an IR Perform TLC analysis ChemDraw Rotovap

Acknowledgements

 Dr. Moses Lee  Drs. Toni Brown & Hilary Mackay  Kristin Dittenhafer  Lee Lab Group  REACH  Hope College Chemistry Department  Conjura Pharmaceuticals, LLC