Synthesis of model morpholine derivatives with biological activities by laccase‐catalysed reactions

Abstract

The efficient enzyme-catalysed reaction of morpholines as model structures for bioactive compounds with para-dihydroxylated aromatic systems was carried out using the oxidoreductase laccase and atmospheric oxygen to produce eight novel morpholine-substituted aromatics. The laccase of Myceliophthora thermophila was used for cross-linking morpholines containing primary or secondary amino groups with para-dihydroxylated laccase substrates. We demonstrate that not only primary amino groups, but also secondary amino groups, are able to couple with para-dihydroxylated aromatic systems in laccase-catalysed reactions. The resulting model products (yields up to 80%) were isolated, structurally characterized and tested for their antibacterial, antifungal and cytotoxic activities. Four of the eight products showed low to moderate growth inhibition against several Gram-positive and -negative bacterial strains and against the yeasts Candida maltosa and Candida albicans. The antibacterial and antifungal activities were determined by an agar disc diffusion test and a modified method according to the EUCAST discussion document E.Dis 7.1 [Rodríguez-Tudela et al. (2003) Clin. Microbiol. Infect. 9, i-viii] for the evaluation of MIC (minimal inhibitory concentration). Differences in cytotoxicity against the human urinary bladder carcinoma cell line 5637 are discussed.

Laccase-mediated multi-step homo- and heteromolecular reactions of ortho -dihydroxylated aromatic compounds and mono- or diaminated substances resulting in C C, C O and C N bonds

“…For reactions of para-dihydroxylated aromatic substances and amino compounds yields of 20-80% are achievable [12] and for optimized reactions a yield of 96% is possible [6].…”

“…Furthermore, this hydroxylated product can undergo a coupling reaction with 3c or 3d as described for the heteromolecular reaction of 2,5-dihydroxy-N-(2-hydroxyethyl)-benzamide and morpholine [12].…”

“…Some of the products may be biologically active e.g. antibacterial [10,11], antifungal [12], antioxidative [13,14] or anticancer [9].…”

Synthesis of New 2-N,N' ­ dialkylamino-1,4-naphthoquinone Derivatives: Concerning the Reactivity of Lapachol with Secondary Amines

“…C NMR chemical shift for C-2 of 2-alkylamino-1,4-naphthoquinones from primary amines ranged from 144.8 ppm to 149.0 ppm, 10,12,17,[21][22][23] and more upfield than those of secondary amines (ranging from 150.6 ppm to 154.0 ppm). 10,[23][24][25][26] From the data in table 3, it can be observed that the C-2 chemical shift of dialkylamino derivatives ranges from 150.0 ppm to 154.1 ppm (5b-e,5j, 6b-h, 6j 28 both using the same methodology, are in reality easily understood if we rationalize they are actually alkyl-and dialkylammonium salts of lapachol and thus are not the result of the claimed substitution reactions. The absence of HMBC correlation between the carbon chain of amine with C-2 further compromises the conclusions put forward by these authors.…”

Benzofuran–Morpholinomethyl–Pyrazoline Hybrids as a New Class of Vasorelaxant Agents: Synthesis and Quantitative Structure–Activity Relationship Study

“…1). The morpholine scaffold is very versatile and was featured in a number of biologically and pharmacologically active products such as vasorelaxant, 17) anticancer, 18) antioxidant, 19,20) analgesic, 21) antimicrobial 22,23) and antiparasitic agents. 24) Mannich bases with morpholinomethyl of synthetic flavonoids exhibited good effects during global ischemia and perfusion in rat brain.…”