Abstract
A tailored series of coumarin-based ferrocenyl 1,3-oxazine hybrid compounds was synthesized and investigated for potential antiparasitic activity, drawing inspiration from the established biological efficacy of the constituent chemical motifs. The structural identity of the synthesized compounds was confirmed by common spectroscopic techniques: NMR, HRMS and IR. Biological evaluation studies reveal that the compounds exhibit higher in vitro antiparasitic potency against the chemosensitive malarial strain (3D7 P. falciparum) over the investigated trypanosomiasis causal agent (T. b. brucei 427) with mostly single digit micromolar IC50 values. When read in tandem with the biological performance of previously reported structurally similar non-coumarin, phenyl derivatives (i.e., ferrocenyl 1,3-benzoxazines and α-aminocresols), structure-activity relationship analyses suggest that the presence of the coumarin nucleus is tolerated for biological activity though this may lead to reduced efficacy. Preliminary mechanistic studies with the most promising compound (11b) support hemozoin inhibition and DNA interaction as likely mechanistic modalities by which this class of compounds may act to produce plasmocidal and antitrypanosomal effects.
Highlights
Malaria and trypanosomiasis are protozoal infections that are endemic in tropical regions
Synthesis of the target compounds was achieved by reductive amination of formyl hydroxycoumarins 9 and 14a–c with ferrocene methylamines 10a,b, prepared according
Synthesis of the target compounds was achieved by reductive amination of formyl hydroxycoumarins 9 and 14a–c with ferrocene methylamines 10a,b, prepared according to literature methods [13,51,52,53,54], that was affected by sodium borohydride as the reducing agent in yields ranging between 66 and 86% (Scheme 1) [55]
Summary
Malaria and trypanosomiasis are protozoal infections that are endemic in tropical regions. Infection of the human host with protozoal Trypanosoma species causes human African trypanosomiasis ( known as sleeping sickness) [3] These diseases are preventable and curable, courtesy of cutting-edge medical technologies of the modern day and the concerted efforts by both the public and private sector, they still pose a great burden to the healthcare sector in developing economies and threaten many lives. Initiatives such as the Medicines for Malaria Venture (MMV) and Drugs for Neglected Diseases Initiative (DNDi) are among the leading programmes of the past decades that spear-headed drug discovery innovation directed towards the Molecules 2021, 26, 1333.
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