Drug Design and Synthesis of New 2-Amino Selenophenes Anti-leishmanial Drugs Candidates

Drug Design and Synthesis of New 2-Amino Selenophenes Anti-leishmanial Drugs Candidates

• Author
• Ricardo Eduardo Pereira Coutinho
• Co-authors
• Francisco Jaime Bezerra Mendonça Junior , Rodrigo Santos Aquino de Araújo
• Abstract

• INTRODUCTION The World Health Organization (WHO) classifies neglected diseases as those related to health and life precariousness. Among these, leishmaniases present themselves as a group of non-contagious infectious diseases (MENDONÇA JÚNIOR; AQUINO, 2015) that can affect the skin, mucous membranes, and internal organs. Depending on the affected area, it has two clinical forms: cutaneous and visceral (RIBEIRO, 2021). Without investment, medicinal alternatives have remained the same for around 50 years, primarily based on pentavalent antimonials, which have already been identified for their toxicity (MENDONÇA JÚNIOR; AQUINO, 2015). Due to the prolonged duration of available treatments, the parasite has specialized, generating new resistant strains (MOMEN; CUPOLILLO, 2000). Therefore, medications with greater efficacy and less toxicity need to be developed. Medicinal chemistry providing new tools for the rational and synthetic planning of new drugs. An example is bioisosterism, which involves the substitution of atoms or molecular groups with others of similar properties and characteristics, aiming to strengthen and improve pharmacological effects (BARREIRO et al., 2002). In the most studied fields of medicinal chemistry, for the search for innovations in bioactive drugs, heterocyclic compounds stand out for their biological potential and can be used as starting points for the development of new therapeutic alternatives (MINDERS et al., 2015). Considering such potentials, thiophenic compounds are examples, consisting of a five-membered aromatic heterocycle containing sulfur (ZONGHAI, 2005) and possessing, among others, leishmanicidal applications (ZAIB et al., 2015). Derivatives of 2-aminothiophenes have been the subject of study by our research group due to their promising anti-Leishmania activities, as demonstrated in various recent publications (OLIVEIRA et al., 2015; RODRIGUES et al., 2018; FÉLIX et al., 2020). These studies have shown the importance and high anti-leishmanial value of 2-aminothiophene moieties, indicating that these can be used as prototypes for structural modifications aimed at improving their pharmacological and/or pharmacokinetic parameters. Among these possible modifications, the substitution of the sulfur atom by selenium emerges as a bioisosteric strategy to obtain new compounds that may prove promising (SOUZA, 2018; SECK, P; THOMAE, D, 2012).

  AIMS In this context, the main objective of this work was to synthesize new 2-amino-selenophene derivatives, bioisosteres of 2-aminothiophene derivatives, in order to evaluate the anti-leishmanial potential of this structural modification.

  MATERIALS AND METHODS For the synthesis of 2-amino-selenophene derivatives, a variation of the classical Gewald reaction was used (PUTEROVÁ, KRUTOSIKIVA; VÉGH, 2009), where sulfur was replaced by selenium. After obtaining and isolating the Gewald adduct, this intermadiate was reacted with equimolar amounts of substituted benzaldehydes, providing the target compounds. All final compounds had their physicochemical properties determined (melting point, Rf, and appearance) and their chemical structures were confirmed by nuclear magnetic resonance (NMR) and infrared (IR).

  RESULTS AND DISCUSSION Seven 2-amino-selenophenes derivatives were successfully obtained with moderate to good yields, ranging from 47% to 66%, in the form of amorphous yellow/red solids. Their chemical properties, Rf values, and melting points were determined. Nuclear Magnetic Resonance (NMR) and Fourier Transform Infrared (FT-IR) spectroscopy confirmed the structures of the compounds, and all characteristic signals of the molecules were observed. In the FT-IR spectroscopic analysis, the main observed signals were the imine stretching (C=N, in regions around 1,600 cm-1), nitrile stretching (CN, in regions around 2,200 cm-1), and aromatic regions (around 700 cm-1 and 1,555 cm-1). In 1H NMR, characteristic chemical shifts for iminic hydrogen were observed (around ? 8.51 ppm), characteristic shifts in the regions of aromatic hydrogens (? between 8.01 and 7.47 ppm), and methylene hydrogens from the cycloheptyl ring linked to the selenophene ring (? between 2.97 and 1.62 ppm), confirming the structure of the final compounds. 

  CONCLUSIONS The synthesis of the new derivatives proved to be efficient, allowing their obtainment in moderate to good yields, and their chemical structures were identified through FT-IR and 1H NMR spectroscopic methods. All these compounds had their physicochemical properties determined and were sent for mass spectrometric to characterization complementation. The compounds were submitted for evaluation of their anti-Leishmania potential, and receiving these results will enable the delineation of structural characteristics that may favor or hinder this biological activity, particularly the bioisosteric substitution of sulfur by selenium.

  ACKNOWLEDGMENTS This work was conducted with the support of CNPq, National Council for Scientific and Technological Development – Brazil, under process number 144478/2022-6; and the support and infrastructure from the State University of Paraíba – Campus V and the Laboratory of Synthesis and Vectorization of Molecules. 

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• Keywords
• 2-Amino-selenophenes; Medicinal Chemistry; Leishmaniasis; Bioisosterism.
• Modality
• Pôster
• Subject Area
• Drug Design and Discovery, Synthesis and Natural Products