N-9 methylated caffeine: An alternate potentially active pharmaceutical ingredient to caffeine and its complexation with β-CD

•Synthesis and characterization of N-9 methylated caffeine.•Self-aggregation property and drug likeness were investigated.•Identical binding at the orthosteric pocket of adenosine receptor.•Complexation with β-CD was also reported.•Potentially active alternate API of caffeine. Caffeine is the most consumable bitter “energy-boosting” natural xanthine alkaloid that works on the central nervous system (CNS) and a good antagonist to adenosine receptors. Its partial aqueous solubility, however limits it to be used efficiently in novel drug formulations. To this endeavour, we have methylated the N-9 position of caffeine. The N-9 methylated caffeine thus formed is highly water soluble and showed attractive drug likeness and ADMET properties. It also docked at the identical orthosteric pocket of the A2A receptors showing H-bond interaction with ASN A:253 residues. It exhibited limited self-aggregation propensity in molecular dynamics simulation studies as against to natural caffeine. We propose this N-9 methylated caffeine as an alternate active pharmaceutical ingredient (API) of natural caffeine. Further, we have modified the texture of the caffeine API to powder form by complexing it with β-CD. A 1:1 inclusion complex (IC) was formed that was characterised by modern spectral techniques like, UV–vis, FT-IR, 1D and 2D NMR, WAXRD and SEM studies. The IC has enhanced thermal stability and is practically nontoxic as revealed in DNA interaction study. All the data indicated the applicability of β-CD as potential vehicle for caffeine-API which may open up new horizons to developing semi-synthetic alternative drug forms.