INTRODUCTION: Giardiasis is a neglected disease, characterized by outbreaks of diarrhea and transmitted by ingestion of contaminated water or food [1,2]. Giardiasis treatments are known to cause several undesirable adverse effects [1,3]. Therefore, there is a need for new molecules with less side effects and better activity against resistant strains. Following the global trend, the molecular hybridization strategy was applied in the synthesis of new compounds [4], for this thymol derivatives produced from the Morita– Baylis–Hillman reaction (MBHR) were used. MBHRs have been studied as drug candidates for many parasites [5] and studies of antiparasitic activity against Giardia lamblia carried out with medicinal plants containing high concentrations of thymol demonstrate that thymol may be responsible [6,7]. AIMS: This work describes the evaluation of the giardicidal activity of 11 thymol derivatives produced from the MBHR reaction. METHODS: The pharmacokinetic and toxicological characteristics were investigated through in silico tests with PASS online and Molinspiration software. Antiparasitic activity was performed against wild-type strains of Giardia lamblia. Furthermore, the cytotoxicity was evaluated using immortalized human cell lines (HEK-293 and HT-29). RESULTS AND DISCUSSION: The in silico prediction showed theoretical bioavailability after oral administration as well as antiparasitic activity against G. lamblia. MBHAs obtained from thymol acrylate, nitro-benzaldehydes and halogenated-benzaldehydes demonstrated a better theoretical pharmacological effect than thymol for antiparasitic activity. Antiparasitic activity against G. lamblia (IC50) of MBHAs thymol/4-nitrobezaldehylde and thymol/4-metoxybezaldehylde were better than thymol. MBHA thymol/4-nitrobezaldehylde showed the best biological activity against G. lamblia, 24 times better than thymol. This MBHA was also obtained in a short reaction time (3 h) with a yield (80%) superior to the other investigated molecules. The literature presents studies that associate this behavior to the presence of the nitro group in molecules [8]. Thymol/4-nitrobezaldehylde was more active than the precursors (thymol and a methylacrylate/4-nitrobezaldehyde-based MBHA) and did not show cytotoxicity against HEK-293 or HT-29 cells. Through these results, it was determined that the giardicidal effect was favored by the molecular hybridization involving thymol. CONCLUSION: This work verified the efficiency of the molecular hybridization technique in the synthesis of new thymol derivatives and lays the groundwork for future research on antiparasitic activity against G. lamblia, presenting a new class of drugs with better antigiardial activity in relation to thymol, acting as a basis for the synthesis of new bioactive molecules. ACKNOWLEDGEMENT: The authors are grateful for financial support from the Brazilian agencies CNPq, FAPEMIG, CAPES, UFPB and UFMG.
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[2] Matadamas-Martinez F et al (2020) Mem Inst Oswaldo Cruz 115:1745–1755.
[3] Dyab AK et al (2016) Parasitol Res 115:2637–2645
[4] Singh G et al (2019) Bioorg Med Chem 27:188–195.
[5] Wei F et al (2015) Org Lett 17:1688–1691
[6] Hezarjaribi HZ et al (2015) Asian Pacific J Trop Dis 5:925–929.
[7] Adame-Gallegos JR et al (2016) J Essent Oil Bear Plants 19:553–567.
[8] Paulai FR et al. (2009) Quim Nova 32:1013–1020.
Comissão Organizadora
Francisco Mendonça Junior
Pascal Marchand
Teresinha Gonçalves da Silva
Isabelle Orliac-Garnier
Gerd Bruno da Rocha
Comissão Científica
Ricardo Olimpio de Moura
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