Synthesis, characterization and antimicrobial evaluation of piperazinyl-quinolinyl-a-aminophosphonates

Abstract

α-Aminophosphonates (α-APs) is an important motif among heterocycles particularly in medicinal chemistry due to their reduced levels of cytotoxicity and structural resemblance to the corresponding α-amino acids. They are useful intermediates in synthetic organic processes and present with a broad spectrum of biological activities. Hence, there is an ongoing interest in the development of improved synthetic methods for the preparation of these α-APs. The complex molecules were initially synthesized in a step-wise reaction but this method suffered several drawbacks such as long reaction times and resulted in low yields. However, since the development of multi-component reactions (MCRs), three or more substrates can undergo an efficient one-pot reaction which results in higher product yields.

The first step in the synthetic aspect of this study involved the preparation of a novel palladium supported strontium titanate (Pd-SrTiO3) material. Herein, an aqueous solution of strontium (II) nitrate was mixed with citric acid followed by reflux in an ethanolic solution of titanium (IV) butoxide. Thereafter, the dried solid was mixed with palladium (II) nitrate and this solution mixture was refluxed, filtered, calcined and subsequently dried. The characterization of Pd- SrTiO3 was undertaken with FT-IR, P-XRD, SEM, BET, SEM-EDX and Raman spectroscopic techniques. The synthesis of a series of novel -αAPs in a MCR system comprising an aldehyde, diethyl phosphate and selected aniline derivatives via the Kabachnik Fields reaction approach in the presence of catalytic amounts of Pd-SrTiO3 was investigated Twenty methyl piperazinyl-quinolinyl α-aminophosphonates (MPQ-α-APs) (4a-4t) were synthesized, purified and characterized by FT-IR, 1H-NMR, 13C-NMR, 31P-NMR, 2D-NMR and high resolution mass spectroscopic techniques. Valuable features of this routine included high yields, extensive substrate range, straight forward procedures and excellent catalytic properties.

The cytotoxicity of 4d, 4e, 4f, 4m, 4q, 4r and 4s was evaluated using the Brine shrimp lethality assay. These compounds showed Artemia salina death < 50 % thereby suggesting their potential for other biological evaluation.

The antimicrobial evaluation was conducted using the agar disc diffusion assay. The twenty MPQ-α-APs were assessed against Bacillus cereus , Staphylococcus aureus , Klebsiella pneumonia and Micrococcus luteus ; and three yeast cultures Candida albicans, Caraipa utilis and Saccharomyces cerevisiae. Compound 4m showed slight bacterial growth inhibition for the test species Bacillus cereus and Micrococcus luteus while compound 4r was marginally inhibitory to the growth of Staphylococcus aureus.

Finally, the MPQ-α-APs were screened for their antioxidant activity by the DPPH assay. Compounds 4f and 4r demonstrated significant free radical scavenging potential of 94.24 % and 67.32 %, respectively. The remaining compounds showed low antioxidant activity within the range of 21 – 42 %.