Pyridine Carboxamides Based on Sulfobetaines: Design, Reactivity, and Biological Activity

Abstract

The synthesis of the products of the 1,3-propanesultone ring opening during its interaction with amides of pyridinecarboxylic acids has been carried out. The dependence of the yield of the reaction products on the position (ortho-, meta-, para-) of the substituent in the heteroaromatic fragment and temperature condition was revealed. In contrast to the meta- and para-substituted substrates, the reaction involving ortho-derivatives at the boiling point of methanol unexpectedly led to the formation of a salt. On the basis of spectroscopic, X-Ray, and quantum-chemical calculation data, a model of the transition-state, as well as a mechanism for this alkylation reaction of pyridine carboxamides with sultone were proposed in order to explain the higher yields obtained with the nicotinamide and its N-methyl analog compared to ortho or meta parents. Based on the analysis of ESP maps, the positions of the binding sites of reagents with a potential complexing agent in space were determined. The in silico evaluation of possible biological activity showed that the synthetized compounds revealed some promising pharmacological effects and low acute toxicity.

Reaction of Picolinamides with Ketones Producing a New Type of Heterocyclic Salts with an Imidazolidin-4-One Ring

“…In solution ( Figure 4 B), the calculated value of the dihedral angle (φ) N1–C–C–N2 is close to zero while in the solid state ( Figure 1 ) it approaches 180°. According to quantum-chemical calculations, the most stable conformation of non-protonated picolinamide 1a is achieved at φ ≈ 0° [ 10 ]. However, this is not the case for protonated picolinamide in 2a , where the conformation with φ ≈ 180° is by ca.…”

“…In contrast to meta- and para-pyridinecarboxamides, their ortho-analogues (picolinamides) react with 1,3-propanesultone in hot methanol to give pyridinium salts with a protonated endocyclic nitrogen atom [ 10 ]. In this work, the scope of this reaction has been extended to other alcohols.…”

“…IR (solid, ν/cm −1 ): 1679 s (C=O), 1604 (C=C pyridine ), 1212, 1108, 1032, (SO 3 ). 1 H-NMR (300.1 MHz, D 2 O, ppm, J/Hz): δ 1.92 (m, 2H, C-CH 2 -C), 2.85 (t, 2H, 3 J = 7.1 CH 2 SO 3 ), 3.50 (t, 2H, 3 J = 7.3, CH 3 O-CH; 2 ), 3.26 (s, 3H, CH 3 O -CH 2 ), 2.95 (s, 3H, HNCH 3 ), 8.12 (t, 1H, 3 J = 7.0, H 5 ), 8.81 (d, 1H, 3 J = 8.1, H 6 ), 8.34 (d, 1H, 3 J = 6.1, H 4 ), 8.63 (t, 1H, 3 J = 7.0, H 5 ); 13 C-NMR (75.5 MHz, D 2 O, ppm): δ 24.03, 26.90, 47.78, 57.61, 70.47, 125.06, 129.57, 143.21, 146.96, 162.39 [ 10 ].…”

“…In our previous works, traditional synthetic approaches [ 9 ] were used for the preparation of novel pyridinecarboxamides ( A ) containing a homotaurin fragment [ 10 ]. Typically, the reactions proceeded through the opening of the sultone ring, as shown in Scheme 1 .…”

“…The low yield of product A in the case of picolinamides and the formation of salt B at high temperatures are likely to be a result of intramolecular bonding in the substrate involving the amido group and endocyclic nitrogen atom [ 10 ].…”