University of South Florida

The Penn State Research Foundation

Niranjan Kumar Namelikonda

Roman Manetsch

Dennis Edward Kyle

David Lawrence Flanigan

Richard Matthew Cross

Hong-Gang Wang

Katya Pavlova Nacheva

Jordany Richarlson Maignan

Megan M Barber

Jeremiah Dwayne Tipton

Alexis Nichole LaCrue

Iredia David Iyamu

Kenichiro Doi

Sameer Shamrao Kulkarni

Tina Susanna Mutka

Fabian Ernesto Saenz

Methods of identifying target binding molecules by target guided synthesis are provided. The methods include providing two or more fragments capable of reacting to form the target binding molecule and mixing the fragments with the target. The methods can be used to identify target binding molecules that bind targets such as proteins or nucleic acids, including those that bind shallow binding pockets on the surface of such targets. The methods are applied to the Bcl-XL and Mcl-1 proteins from the Bcl-2 family of proteins. Using thio acid and sulfonyl azide fragments capable of reacting through sulfo-click chemistry, new acyl sulfonamides are identified that bind one or both of the Bcl-XL and Mcl-1 proteins. Pharmaceutical formulations of these target binding molecules are also provided.

Target binding molecules identified by kinetic target-guided synthesis

Provided are 4(1H)-quinolone derivatives effective in inhibiting or eliminating the viability of at least one of the stages in the life-cycle of the malarial parasite, and to show a reduced propensity to induce resistance to the compound by the target parasite. In particular, the compounds can be derivatives of phenoxyethoxy-quinolones, and including, but not only, 7-(2-phenoxyethoxy)quinolin derivatives. These compounds may be administered by themselves, with at least one other derivative compound, or with other antimalarial compounds, to an animal or human subject. The therapeutic compositions can be and formulated to reduce the extent of ainfection in the recipient subject, or to reduce the likelihood of the onset or establishment of ainfection if administered prior to the parasite contacting the subject. The therapeutic compositions can be formulated to provide an effective single dose amount of an antimalarial compound or multiple doses for administering over a period of time.

4(1H)-quinolones having antimalarial activity with reduced chemical resistance

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Niranjan Kumar Namelikonda