Synthesis and evaluation of 2-phenylamino-1,4-naphthoquinones derivatives as potential hypoglycaemic agents

Abstract

Due to the severe side effects revealed by most of the currently used antidiabetic medicines, search for finding new and safe drugs to manage diabetes is continued. Naphthoquinones possessing strong antioxidant properties have been employed as candidates for diabetes therapy. Present study is aimed at finding the antioxidant and hypoglycaemic potential of some novel derivatives of 2-phenylamino-1,4-naphthoquinones (PAN) including chloro, nitro, methyl and bromo (5a-d) derivatives synthesized by single pot experiment. Product crystals were purified by TLC and characterized by FT-IR. The antioxidant potential of the compounds was assayed through DPPH radical scavenging and reducing power activities noted as UV-vis. absorbance. The DPPH assay has showed the powerful antioxidant activity of nitro and bromo derivatives, while the nitro derivative showed the significant reduction potential towards FRAP assay. Hypoglycaemic potential of the compounds was studied in rat animal model. All synthesized compounds revealed better hypoglycaemic activity; however, the chloro-derivative exhibited the more potent hypoglycaemic activity showing about 43% reduction in the mean blood glucose levels of the treated animals. As the bioreduction of naphthoquinones may be influenced by changing its redox properties, it has been noticed that the e-donating resonance effect (+R) of ‘chloro’ group has shown the significant effects on biological activity through stabalization of its imine form which limits the potential of generation of free radicals during bioreduction of quinones and thus has been proposed as the reason of its hypoglycaemic activity. Future studies employing the properties of e-donating groups of PAN may optimize the drug-receptor interaction for better drug designing and drug development strategies against diabetes and also for the clinical trials.

Blue Light Irradiated Metal-, Oxidant-, and Base-Free Cross-Dehydrogenative Coupling of C(sp2)–H and N–H Bonds: Amination of Naphthoquinones with Amines

“…5-Hydroxy-1,4-naphthoquinone (220 mg, 1.26 mmol) and butylamine (150 μL, 1.5 mmol) in methanol (10 mL) gave C­( sp 2 )–N coupled 2,5-regioisomer 65 as an orange solid (observed mp: 152–153 °C; literature 155–156 °C). Yield 160 mg (52% at 1.26 mmol scale, reaction time: 2.0 h) using hexane/EtOAc (80:20) as eluent.…”

“…Also the 2,8-regioisomer 66 was isolated as a red solid (observed mp: 118–120 °C; literature 125–126 °C). Yield 123 mg (40% at 1.26 mmol scale, reaction time: 2.0 h) using hexane/EtOAc (60:40) as eluent.…”

“…Three major synthetic strategies have been used for synthesizing 2-amino-1,4-naphthoquinone until now, one of which involves the nucleophilic displacement of the halo group in quinone with amines, ,,, while the second involves a direct 1,4-addition of amines to the quinones, ,, and the third strategy utilized metal catalyzed C–H functionalization of 1,4-naphthoquinone with an amine. ,,, However, the developed methodologies require strong acidic conditions, high temperature, metal catalysts, stoichiometric quantities of oxidant, or a strenuous process and also provide lower yields (Scheme ). ,,,− …”

The Relevance and Insights on 1,4-Naphthoquinones as Antimicrobial and Antitumoral Molecules: A Systematic Review

“…Moreover, Razaque et al, 2022, prepared four 4-R-PAN by single pot synthesis with no catalyst, in 69-79% yield. Donating groups in the aniline favor the Michael addition [41] (Figure 4). Leyva et al, 2017, synthesized anilino (PAN: phenylamino naphthoquinone) and dianilino derivatives.…”

“…Moreover, Razaque et al, 2022, prepared four 4-R-PAN by single pot synthesis with no catalyst, in 69-79% yield. Donating groups in the aniline favor the Michael addition [41] (Figure 4). Some PANs have been used as starting materials to prepare novel 1,4-naphthoquinone sulfonamide and sulfonate ester derivatives in good yield, as shown in Figure 5 [42].…”