Novel Benzotriazole-β-lactam Derivatives as Antimalarial Agents: Design, Synthesis, Biological Evaluation and Molecular Docking Studies
Dr. Malihe Aye
Department of Chemistry, College of Sciences, Shiraz University, Shiraz, 71946-84795 Iran
Department of Civil and Environmental Engineering, Shiraz University, Shiraz, Iran
Search for more papers by this authorCorresponding Author
Prof. Aliasghar Jarrahpour
Department of Chemistry, College of Sciences, Shiraz University, Shiraz, 71946-84795 Iran
Search for more papers by this authorDr. Zahra Haghighijoo
Department of pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, 77555 USA.
Search for more papers by this authorCorresponding Author
Dr. Roghayeh Heiran
Estahban Higher Education Center- Shiraz University, Estahban, Iran
Search for more papers by this authorDr. Roya Pournejati
Department of Biology, College of Sciences, Shiraz University, PO Box: 71467-13565, Shiraz, 71454 Iran
Search for more papers by this authorDr. Hamid Reza Karbalaei-Heidari
Department of Biology, College of Sciences, Shiraz University, PO Box: 71467-13565, Shiraz, 71454 Iran
Search for more papers by this authorDr. Veronique Sinou
Aix Marseille Univ, INSERM, SSA, MCT, Faculté de Pharmacie, 27 bd Jean Moulin, 13385 Marseille, France
Search for more papers by this authorProf. Jean Michel Brunel
Aix Marseille Univ, INSERM, SSA, MCT, Faculté de Pharmacie, 27 bd Jean Moulin, 13385 Marseille, France
Search for more papers by this authorProf. Mehmet Akkurt
Department of Physics, Faculty of Sciences, Erciyes University, 38039, Kayseri, Turkey
Search for more papers by this authorDr. Namık Özdemir
Division of Physics Education, Department of Mathematics and Science Education, Faculty of Education, Ondokuz Mayıs University, TR-55139 Samsun, Turkey
Search for more papers by this authorProf. Edward Turos
Center for Molecular Diversity in Drug Design, Discovery, and Delivery, Department of Chemistry, CHE 207, 4202 East Fowler Avenue, University of South Florida, Tampa, FL 33620 USA
Search for more papers by this authorDr. Malihe Aye
Department of Chemistry, College of Sciences, Shiraz University, Shiraz, 71946-84795 Iran
Department of Civil and Environmental Engineering, Shiraz University, Shiraz, Iran
Search for more papers by this authorCorresponding Author
Prof. Aliasghar Jarrahpour
Department of Chemistry, College of Sciences, Shiraz University, Shiraz, 71946-84795 Iran
Search for more papers by this authorDr. Zahra Haghighijoo
Department of pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, 77555 USA.
Search for more papers by this authorCorresponding Author
Dr. Roghayeh Heiran
Estahban Higher Education Center- Shiraz University, Estahban, Iran
Search for more papers by this authorDr. Roya Pournejati
Department of Biology, College of Sciences, Shiraz University, PO Box: 71467-13565, Shiraz, 71454 Iran
Search for more papers by this authorDr. Hamid Reza Karbalaei-Heidari
Department of Biology, College of Sciences, Shiraz University, PO Box: 71467-13565, Shiraz, 71454 Iran
Search for more papers by this authorDr. Veronique Sinou
Aix Marseille Univ, INSERM, SSA, MCT, Faculté de Pharmacie, 27 bd Jean Moulin, 13385 Marseille, France
Search for more papers by this authorProf. Jean Michel Brunel
Aix Marseille Univ, INSERM, SSA, MCT, Faculté de Pharmacie, 27 bd Jean Moulin, 13385 Marseille, France
Search for more papers by this authorProf. Mehmet Akkurt
Department of Physics, Faculty of Sciences, Erciyes University, 38039, Kayseri, Turkey
Search for more papers by this authorDr. Namık Özdemir
Division of Physics Education, Department of Mathematics and Science Education, Faculty of Education, Ondokuz Mayıs University, TR-55139 Samsun, Turkey
Search for more papers by this authorProf. Edward Turos
Center for Molecular Diversity in Drug Design, Discovery, and Delivery, Department of Chemistry, CHE 207, 4202 East Fowler Avenue, University of South Florida, Tampa, FL 33620 USA
Search for more papers by this authorAbstract
Many people around the world suffer from malaria, especially in tropical or subtropical regions. While malaria medications have shown success in treating malaria, there is still a problem with resistance to these drugs. Herein, we designed and synthesized some structurally novel benzotriazole-β-lactams using 2-(1H-benzo[d][1,2,3]triazol-1-yl)acetic acid as a key intermediate. To synthesize the target molecules, the ketene-imine cycloaddition reaction was employed. First, The reaction of 1H-benzo[d][1,2,3]triazole with 2-bromoacetic acid in aqueous sodium hydroxide yielded 2-(1H-benzo[d][1,2,3]triazol-1-yl)acetic acid. Then, the treatment of 2-(1H-benzo[d][1,2,3]triazol-1-yl)acetic acid with tosyl chloride, triethyl amine, and Schiff base provided new β-lactams in good to moderate yields.The formation of all cycloadducts was confirmed by elemental analysis, FT-IR, NMR and mass spectral data. Moreover, X-ray crystallography was used to determine the relative stereochemistry of 4a compound. The in vitro antimalarial activity test was conducted for each compound against P. falciparum K1. The IC50 values ranged from 5.56 to 25.65 μM. A cytotoxicity profile of the compounds at 200 μM final concentration revealed suitable selectivity of the compounds for malaria treatment. Furthermore, the docking study was carried out for each compound into the P. falciparum dihydrofolate reductase enzyme (PfDHFR) binding site to analyze their possible binding orientation in the active site.
Graphical Abstract
Conflict of interest
The authors declare no conflict of interest.
Open Research
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
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