A Promising Schistosomicidal Agent

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Spectrophotometric PKA Determination Using SiriusT3 of a New Chemical Entity LPSF/FZ4: A. Promising Schistosomicidal Agent. G. R. Medeiros 1, D. D. Sun 2, ...
Spectrophotometric PKA Determination Using SiriusT3 of a New Chemical Entity LPSF/FZ4: A Promising Schistosomicidal Agent G. R. Medeiros 1, D. D. Sun 2, P. I. Lee 2, L. A. Rolim 1, P. J. Rolim-Neto 1, S. M. Costa 1, M. C. Lima 1, I. R. Pitta 1, J. F. Oliveira 1 1 Federal University of Pernambuco, 2 University of Toronto Purpose To determine the pKa of a poorly water-soluble new chemical entity LPSF/FZ4, which is a heterocyclic imidazolidinic derivative and presents a promising schistosomicidal activity, aiming to deepen the knowledge of the molecule in order to design an adequate formulation of solid dosage form for oral drug delivery. Methods Using the Fast UV titration pka method in SiriusT3 (East Sussex, UK), the pKa values of LPSF/FZ4 were spectrophotometrically determined in approximately 5 mins at different percentages of mixtures of dimethylsulfoxide(DMSO)-water (DMSO 20 to 40% v/v) due to its poor aqueous solubility. The pKa value of this compound was calculated by extrapolation using Yasuda-Shedlovsky equation. A theoretical analysis of the molecular structure and experimental results were used to identify the nature of the pKa found and the ionizable group of the molecule. Results It was found that LPSF/FZ4 is a monoprotic weak base (BH+) with a carbonyl group in position 4 of the imidazolidinic ring with a pKa of 8.48. The experimental value of pKa was compared with the predicted value obtained by SPARC online calculator (pKa = 8.98), and a difference of about 0.5 was found between the values of pKa obtained. When pH is higher than 8.48, the LPSF/FZ4 is predominantly in its neutral form (B). When the pH decreases, the base begins to be protonated (BH+), increasing its solubility. Thus, it was realized that the prototype probably would have a higher solubility in a lower pH environment throughout the gastrointestinal tract. The discovered pKa should affect the solubility, permeability and logP by modulating the distribution of neutral and charged species, facilitating the oral absorption and showing the viability of LPSF/FZ4 as a drug candidate for oral delivery. Conclusion The results obtained in this study, such as the pka of the prototype, its ionizable group and a better understanding of its behavior in solution, were of enormous importance, to provide relevant information for a rational drug formulation design with the new chemical entity LPSF/FZ4, an alternative for treatment of Schistosomiasis, a predominant neglected disease in many developing nations.