Synthesis, characterization and larvicidal studies of ethyl 3-benzoyl-7-(piperidin-1-yl)indolizine-1-carboxylate analogues against Anopheles arabiensis and cheminformatics approaches

Abstract

According to WHO, in 2021, there was an estimation of 247 million malaria cases from 84 malaria-endemic countries. Globally an estimated count of 2 billion malaria cases and 11.7 million deaths due to malaria were recorded in the past two decades. Further, the emergence of drug-resistant mosquitos threatens mankind. Therefore, the development of newer larvicidal agents is the need of the hour. This research identifies a new series of variably substituted indolizines for their effectiveness in controlling Anopheles arabiensis larvae through larvicidal activity. The series of Ethyl 3-benzoyl-7-(piperidin-1-yl)indolizine-1-carboxylate analogues (4a-j) were synthesized by reacting 4-(piperidin-1-yl)pyridine, phenacyl bromides with ethyl propiolate via 1, 3-dipolar cycloaddition and the green metrics of the process are reported. All the newly synthesized compounds were characterized by spectroscopic techniques such as ¹H NMR,¹³C NMR, FT-IR, and HRMS. The larvicidal effectiveness of the newly synthesized compounds was assessed against Anopheles arabiensis. Among the compounds studied, namely 4c, 4d, 4e, and 4f, displayed the most notable larval mortality rates within the series, reaching 73%, 81%, 76%, and 71% respectively, in contrast with the negative control acetone. In comparison, the standard Temephos exhibited a mortality rate of 99% at the same concentration. Furthermore, computational approaches including molecular docking and molecular dynamics simulations identified the potential targets of the series compounds as the larval Acetylcholinesterase (AChE) enzyme and the Sterol Carrier Protein-2 (SCP-2) protein. However, it is essential for these computational predictions to undergo experimental validation.

Communicated by Ramaswamy H. Sarma

Keywords:

• Indolizine
• larvicidal agent
• Anopheles arabiensis
• acetylcholinesterase (AChE) enzyme
• sterol carrier protein-2 (SCP-2) protein
• ADME

Acknowledgements

The authors are grateful to Dr. Shubhini A. Saraf, Director of NIPER Raebareli, and Dr. USN Murty, Former Director of NIPER Raebareli for supporting and encouraging this research work. The authors are thankful to the Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, and Government of India for providing fellowship. VM and KNV thank the Durban University of Technology and the National Research Foundation (129330), South Africa, for their support and encouragement. The authors are also thankful to CIF, NIPER Raebareli for recording the spectra of synthesized compounds. NIPER-R/Communication/490.

Disclosure statement

The authors declare no conflict of interest.

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Funding

The author(s) reported there is no funding associated with the work featured in this article.