Facile synthesis and stereochemical investigation of Mannich base derivatives: evaluation of antioxidant property and antituberculostic potency

A mini-library of diversely substituted 2,4-diaryl-3-azabicyco3.3.1]nonan-9-one O-methyloximes and their N-methyl analogs were synthesized by a non-laborious, modified and an optimized Mannich condensation in good yields. Both the ring N-methylation and oxime O-methylation were employed by various methods; of them, the usage of ^tBuOK was found to be the superior in terms of good yield in short time. Stereochemistry of all the synthesized compounds was unambiguously established by their NMR spectral (¹H, ¹³C, ¹H-¹H COSY, ¹H-¹³C one and multiple bond COSY and NOESY) as well as single-crystal XRD studies. Irrespective of the nature and position of the substituents, all the synthesized oxime ethers of the bicyclic Mannich bases as well as their N-methyl analogs adopted the twin-chair conformation with equatorial orientations of all the substituents. All the synthesized oxime ethers were evaluated for their antioxidant property by DPPH radical scavenging method. According to the structure-activity correlations, compound 4y was found to be a lead molecule with the IC₅₀ of 0.187 mg/mL. Thus, the present study exploits the scope of finding more active analogs by further optimization with the incorporation of more electron enriched alkoxy/amino and/or phenolic groups on the heterocycle as well as oxime ether pharmacophore. Most of the synthesized molecules were screened for their antituberculostic potency against Mycobacterium tuberculosis H₃₇Rv by zone of inhibition method. Of them, 4w/5d and 4x showed very promising inhibition zones of 21 and 23 mm, respectively, which leads to the optimization of 4x by introducing various substituents on the O-benzyl moiety to enhance the antituberculostic potency.