Isatin-1,2,3-triazole derivatives: Synthesis, molecular docking and evaluation against acute experimental toxoplasmosis

Fadwa M Arafa; Nehal N Hezema; Ateyatallah Aljuhani; Mohamed R Aouad; Mohamed Hagar; Ahmed Zakaria; Nadjet Rezki; Marwa M Shaaban; Sara A Abdel Salam

doi:10.1016/j.actatropica.2024.107471

Isatin-1,2,3-triazole derivatives: Synthesis, molecular docking and evaluation against acute experimental toxoplasmosis

Acta Trop. 2024 Nov 13:260:107471. doi: 10.1016/j.actatropica.2024.107471. Online ahead of print.

Authors

Fadwa M Arafa¹, Nehal N Hezema², Ateyatallah Aljuhani³, Mohamed R Aouad³, Mohamed Hagar⁴, Ahmed Zakaria⁵, Nadjet Rezki³, Marwa M Shaaban⁶, Sara A Abdel Salam²

Affiliations

¹ Department of Medical Parasitology, Faculty of Medicine, Alexandria University, Alexandria, 21577, Egypt. Electronic address: f_arafa10@alexmed.edu.eg.
² Department of Medical Parasitology, Faculty of Medicine, Alexandria University, Alexandria, 21577, Egypt.
³ Department of Chemistry, College of Science, Taibah University, Al-Madinah Al-Munawarah, 30002, Saudi Arabia.
⁴ Department of Chemistry, Faculty of Science, Alexandria University, Alexandria, 21321, Egypt; Department of Chemistry, Faculty of Advanced Basic Sciences, Alamein International University, Alamein City, Matrouh, Egypt.
⁵ Department of Chemistry, Faculty of Science, Alexandria University, Alexandria, 21321, Egypt.
⁶ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt.

PMID: 39542154
DOI: 10.1016/j.actatropica.2024.107471

Abstract

Toxoplasmosis remains a challenge for both public health and animal husbandry which created a constant demand to develop novel compounds using innovative methods. To join this relentless quest for an ideal chemotherapeutic agent, herein, we developed newly synthesized isatin-1,2,3-triazole derivatives. Three compounds (5a, 5b and 5c) were synthesized, characterized, loaded on chitosan nanoparticles (CNPs) and then evaluated accordingly. Initially, a molecular docking study was carried out which revealed the effective interaction with the target enzymes; purine nucleoside phosphorylase (PNPase) and T. gondii calcium-dependent protein kinase-1 (TgCDPK1). This was further substantiated by in vivo evaluation of the three compounds (5a-c) and their nanoformulae (5a-CNPs, 5b-CNPs, and 5c-CNPs) against acute Toxoplasma gondii infection in murine model. It is worthy of note that all tested compounds and their nanoformulae produced a statistically significant reduction of parasite burden in both peritoneal fluid and liver impression smear and profound ultrastructural alterations, detected by scanning electron microscopy, compared to the infected non-treated control. The nanoformula 5c-CNPs yielded the most outstanding results with the highest tachyzoite reduction percentage in both peritoneal fluid (98.1%) and liver impression smear (95.3%). Furthermore, the serum levels of liver enzymes (aspartate transaminase (AST) and alanine transaminase (ALT), and renal function tests (urea and creatinine) in mice were within normal limits which makes them more appealing candidates with proven safety. To the best of our knowledge, the present work is the first in silico and in vivo study proving the anti-Toxoplasma effect of isatin-1,2,3- triazoles which paves the way for further development of isatin and triazole-based leads for the treatment of toxoplasmosis.

Keywords: Click chemistry; Isatin-1,2,3-Triazole; Molecular docking; Purine nucleoside phosphorylase; T. gondii calcium-dependent protein kinase-1; Toxoplasma gondii.