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Dissertation
Synthesis and optimization of novel amides using the Ugi reaction for anti-malarial screening
Doctor of Philosophy (Ph.D.), Drexel University
May 2010
DOI:
https://doi.org/10.17918/etd-3441
Abstract
The primary goal of this work was to easily synthesize a library of diamides predicted to be potential anti-malarial agents. This thesis focuses on synthesis of those diamides by the Ugi reaction and further optimization studies. Solubility of the reactants and the Ugi product has been used to optimize the reaction. During the preliminary phase we focused on the synthesis of a library of active compounds obtained from Find-A-Drug, a non-profit computing project which serves to address a number of diseases. Although we were unable to synthesize any of the compounds from the Find-A-Drug library, the diamide nucleus served as 'pharmacophore' for the later libraries that were develop in collaboration with computational chemists. Some of the diamides synthesized showed promising results when tested for bio-activity against the plasmodium enzyme, falcipain-2. However, during the synthetic process of these diamides via the Ugi reaction it became clear that not every compound from the library could be synthesized by one general method. One major issues encountered was related to solubility of starting materials in methanol, the usual choice of solvent used for the Ugi reaction. Therefore, optimization studies were carried out to estimate the best solvent and conditions required in order to obtain a better yield with crystalline product, which would not require further chromatographic purification. In one of the optimization studies involving benzaldehyde, furfurylamine, boc-glycine and tert-butylisocyanide best results in terms of yield were obtained when the reaction was performed at 0.4M concentration per component in methanol with 1.2eq imine. This was a significant improvement compared to the reaction performed under equimolar conditions with a 49% yield. Apart from solubility, reaction kinetics and solvent effects which played major role in the final yield of the reaction were also studied. In essence we postulate that knowing the kinetics and 'by being able to predict the solubility of starting materials and products, one can predict the optimal solvent and concentration to carry out the reaction and isolate the Ugi product by simple filtration.
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Details
- Title
- Synthesis and optimization of novel amides using the Ugi reaction for anti-malarial screening
- Creators
- Khalid Baig S. Mirza - DU
- Contributors
- Jean-Claude Bradley (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Arts and Sciences; Chemistry; Drexel University
- Other Identifier
- 3441; 991014632245804721