A new type of quinoxalinone derivatives affects viability, invasion, and intracellular growth of Toxoplasma gondii tachyzoites in vitro
- 384 Downloads
Quinoxalinone derivatives, identified as VAM2 compounds (7-nitroquinoxalin-2-ones), were evaluated against Toxoplasma gondii tachyzoites of the RH strain. The VAM2 compounds were previously synthesized based on the design obtained from an in silico prediction with the software TOMOCOMD-CARDD. From the ten VAM2 drugs tested, several showed a deleterious effect on tachyzoites. However, VAM2-2 showed the highest toxoplasmicidal activity generating a remarkable decrease in tachyzoite viability (in about 91 %) and a minimal alteration in the host cell. An evident inhibition of host cell invasion by tachyzoites previously treated with VAM2-2 was observed in a dose-dependent manner. In addition, remarkable alterations were observed in the pellicle parasite, such as swelling, roughness, and blebbing. Toxoplasma motility was inhibited, and subpellicular cytoskeleton integrity was altered, inducing a release of its components to the soluble fraction. VAM2-2 showed a clear and specific deleterious effect on tachyzoites viability, structural integrity, and invasive capabilities with limited effects in host cells morphology and viability. VAM2-2 minimum inhibitory concentration (MIC50) was determined as 3.3 μM ± 1.8. Effects of quinoxalinone derivatives on T. gondii provide the basis for a future therapeutical alternative in the treatment of toxoplasmosis.
KeywordsApicomplexan Toxoplasma gondii Pellicle Quinoxalinone derivatives In silico drug design TOMOCOMD-CARDD
Electron micrographs were obtained at the Electron Microscopy Unit (LANSE-CINVESTAV), México. The authors acknowledge Corinne Mercier (Université Joseph Fourier, Grenoble, France) for sharing antibodies. Animals were provided by the Animal Facility (UPEAL-LaNSE) at CINVESTAV, Mexico.
Compliance with ethical standards
Research was supported by a grant from the Consejo Nacional de Ciencia y Tecnología (CONACyT, Grant # 155459 to RMF). CRF, RMG, CGL, and KCE were supported by doctoral fellowships, number # 424851, # 394378, # 324983, and # 369769 from CONACyT-México, respectively.
Conflict of interest
The authors declare that they have no conflict of interest.
- Dannemann B, McCutchan JA, Israelski D, Antoniskis D, Leport C, Luft B, Nussbaum J, Clumeck N, Morlat P, Chiu J, Vilde JL, Orellana M, Feigal D, Bartok A, Heseltine P, Leedom J, Remington J (1992) Treatment of toxoplasmic encephalitis in patients with AIDS. A randomized trial comparing pyrimethamine plus clindamycin to pyrimethamine plus sulfadiazine. The California Collaborative Treatment Group. Ann Intern Med 116(1):33–43CrossRefPubMedGoogle Scholar
- Martins-Alho MA, Marrero-Ponce Y, Barigye SJ, Meneses-Marcel A, Machado-Tugores Y, Montero-Torres A, Gómez-Barrio A, Nogal JJ, García-Sanchez RN, Vega MC, Rolon M, Martínez-Fernandez AR, Escario JA, Pérez-Gimenez F, García-Domenech R, Rivera N, Mondragón R, Mondragón M, Ibarra-Velarde F, López-Arencibia A, Martin-Navarro C, Lorenzo-Morales J, Cabrera-Serra MG, Pinero J, Tytgat J, Chicharro R, Aran VJ (2014) Antiprotozoan lead discovery by aligning dry and wet screening: prediction, synthesis, and biological assay of novel quinoxalinones. Bioorg Med Chem 22(5):1568–1585CrossRefPubMedGoogle Scholar
- McCabe RE (2001) Toxoplasmosis: a comprenhensive clinical guide. Cambridge Univ Press, LondonGoogle Scholar
- Muñiz-Hernández S, González-del Carmen M, Mondragón M, Mercier C, Cesbron MF, Mondragón-Gonzalez SL, González S, Mondragón R (2011) Contribution of the residual body in the spatial organization of Toxoplasma gondii tachyzoites within the parasitophorous vacuole. J Biomed Biotechnol 2011:473983CrossRefPubMedPubMedCentralGoogle Scholar
- Rivera-Borroto OM, Marrero-Ponce Y, Meneses-Marcel A, Escario JA, Gómez-Barrio A, Arán V, Martins-Alho MA, Montero-Pereira D, Nogal JJ, Torrens F, Ibarra-Velarde F, Vera-Montenegro Y, Huesca-Guillén A, Rivera N, Vogel C (2009) Discovery of novel trichomonacidals using LDA-driven QSAR models and bond-based bilinear indices as molecular descriptors. QSAR Comb Sci 28(1):9–26CrossRefGoogle Scholar