Novel Pyrimethamine Based Anti-protozoan Agents Utilizing Isostere and Heuristic Structure-similarity Search

Aims: To generate new medicaments for control and treatment of  the parasitic  protozoan Toxoplasma gondii.

Study Design: Structure similarity search and isostere search was conducted over a broad range of structure categories. Correlation and highest similarity scores were implemented to select the best drug candidates.

Place  and  Duration  of  Study: University of Nebraska, Department of Chemistry, Durham Science Center, 6001 Dodge Street, Omaha Nebraska 68182, from June 2016 to February 2017.

Methodology: Utilizing pyrimethamine as the parent compound, a broad range of similar structures and isosteres were found by applying search methods. The compounds having the highest correlation and similarity scores were selected for the study of molecular properties. The molecular properties were determined and examined for underlying relationships by pattern recognition hierarchical cluster analysis and K-means cluster analysis.

Results: Thirty compounds were identified to have a very high level of structure similarity or isosteric relationship to pyrimethamine. The molecular structures and molecular properties are presented for all compounds, inclusive of pyrimethamine. Hierarchical cluster analysis and K-means cluster analysis indicated compounds with highest underlying similarity to pyrimethamine. Box plots showed the over-all distribution of important pharmaceutical properties, such as molecular weight, Log P, polar surface area, number of rotatable bonds, molecular volume, and number of hydrogen bond donors. Structure components are compared to elucidate potential clinical activity. Multiple regression is applied on all compounds to generate a numerical relationship for prediction of similar compounds. Save for only one  isostere, all  compounds  showed  zero  violations  of  the  Rule  of  5,  indicating  favorable  drug-likeness and bioavailability.

Conclusion: Thirty compounds highly analogous to pyrimethamine were identified following heuristic search course. The molecular properties were determined for all compounds and indicated genuine potential  for treatment  of  toxoplasmosis.  Correlation  of  structure  and  pattern  recognition methods indicated 30 compounds of clinical potential and property analogy to pyrimethamine. All compounds in this study showed favorable bioavailability, having zero violations of the rule of 5. Hierarchical cluster analysis  and  K-means  cluster  analysis  showed  that  the  isostere  compounds  were  most  similar  to pyrimethamine. Multiple regression analysis produced a mathematical model for predicting properties of compounds of similar medicinal use. The study and design of new medicinal agents for treatment of protozoan infections is a vital endeavor with great demand in the future.

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