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Synthesis, Cytotoxic Activity on Leukemia Cell Lines and Quantitative Structure-Activity Relationships (QSAR) Studies of Morita-Baylis-Hillman Adducts

[ Vol. 12 , Issue. 7 ]


Claudio G. Lima–Junior, Gláucia V. Faheina–Martins, Caio C. B. Bomfim, Bruna B. Dantas, Everton P. Silva, Demetrius A. M. de Araújo, Edilson B. A. Filho and Mário L. A. A. Vasconcellos   Pages 602 - 612 ( 11 )


Background: The Morita-Baylis-Hillman reaction is an organocatalyzed chemical transformation that allows access to small poly-functionalized molecules and has considerable synthetic potential and promising biological profiles. The Morita–Baylis–Hillman adducts (MBHA) are a new class of bioactive compounds and highlight its potentialities to the discovery of new cheaper and efficient drugs, e.g. as anti-Leishmania chagasi and Leishmania amazonensis, anti- Trypanosoma cruzi, anti-Plasmodium falciparum and Plasmodium berghei, lethal against Biomphalaria glabrata, antibacterial, antifungal, herbicide and others.

Methods: The goal of this work is to describe the primary cytotoxic activities against strains of human leukemia HL-60 cell line for thirty-four Morita-Baylis- Hillman adducts (MBHA), followed by a Quantitative Structure-Activity Relationships study (QSAR).

Results: The conventional or microwave–assisted syntheses of MBHA, derived from substituted aromatics or Isatin, were performed in good to excellent yields (70-100%) in short reaction times, using protocols recently developed by us. Isatin derivatives, MBHA 31 and 32, were the most active in this congener series of compounds, with IC50 values of 10.8 M and 7.8 M, respectively. The primary cytotoxic activities against chronic leukemia cells (K562) were also evaluated to these two most active compounds (MBHA 31 and 32), presenting IC50 values of 53 M and 43 M respectively. QSAR study was performed considering 3D, 2D and constitutional molecular descriptors. These were selected from Ordered Predictor Selection algorithm and submitted to Partial Least Squares Modeling.

Conclusion: We present an interesting investigation about cytotoxic activities on human leukemia cell line (HL–60) for 34 synthetic MBHA. In a good way we discovered that the most cytotoxic compounds (31–32, 10.8 M and 7.8 M respectively) were also prepared quantitatively (100% yields) in a short reaction time using microwave irradiation. We demonstrate that 31 and 32 induced apoptosis and not necrosis in HL-60 cells, observed by externalization of PS and increase Anexin-V positive cells. Quantitative Structure-Activity Relationships considering 3D, 2D and constitutional descriptors provided a robust and predictive PLS model, in accordance with SAR observations.


Morita-Baylis-Hillman adducts, cytotoxic activities, leukemia, QSAR.


Laboratório de Síntese Orgânica Medicinal da Paraíba (LASOM-PB), Departamento de Química, Universidade Federal da Paraíba, Campus I, João Pessoa, PB 58059-900, Brazil.

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