Hydrogen bonding nicotinamides

A co-crystal of celecoxib with nicotinamide (Vitamin B3) was identified [49]. The co-crystal has a 1 1 stoichiometry and is comprised of hydrogen bonded nicotinamide dimers that sit within channels formed by celecoxib molecules, as elucidated by powder diffraction structure determination (Figure 3.5). The form rapidly dissociates when dispersed in aqueous solutions and the parent, celecoxib, precipitates in one of several forms depending on the excipients present. Although complex, the dissolution behaviour of the co-crystal has been evaluated and through the use of a spring and parachute approach, the in vitro performance of celecoxib nicotinamide was shown to be superior to that of the parent compound. 

Nicotinamide, (S)-N-(a-methylbenzyl)-hydrogen bonding, 2, 111 Nicotinamide, N-phenyl-hydrogen bonding, 2, 111 Nicotinamide adenine dinucleotide in biochemical pathways, 1, 248 coenzyme system with NADH, 2, 121 reactions, 2, 382 reduction, 2, 281, 283... 

Most PARPi are based upon nicotinamide (1), the by-product of the PARylation reaction, which itself is a micromolar PARPi. PARPi have been developed using three design approaches constraining the amide using an internal hydrogen bond, forming a lactam, and incorporation of the amide into a heterocycle [3,15]. 

Figure 15-4 The nicotinamide ring of NADH in a syn boat conformation suitable for transfer of an axially oriented pro-R hydrogen atom from its A face as H-. The flow of electrons is shown by the solid arrows. The dashed arrows indicate competing resonance which favors planarity of the ring and opposes the H transfer. Hydrogen bonds from the protein to the carboxamide group (dashed lines) affect both this tendency and the conformation of the nucleotide.

The 2.9 A resolution structure reveals that the NADH is bound in the enzyme binding domains by an extensive series of hydrogen bonds through the oxygen atoms of the pyrophosphate and the amide group of the nicotinamide. However, no atom in the coenzyme molecule is within bonding distance of the active site zinc atom, the closest being 4.5 A from the metal ion. 

It was observed that needle-like crystals of the metastable Form-II of the carbamazepine-isonicotinamide cocrystal formed when the ingredients were initially dissolved in ethanol, but that over time plate-like crystals of the stable Form-I grew in the suspension [44]. It was concluded that the molecular packing in Form-II consisted of carbamazepine dimers hydrogen-bonded to nicotinamide chains, and where the pyridine nitrogen of isonicotinamide did not participate in the hydrogen bonding. 

It has been reported that a 1 1 nicotinamide and ethyl paraben (ethyl 4-hydroxybenzoate) cocrystal can be crystallized from ethanol, with the crystal structure being used to demonstrate that both reactant molecules form corrugated layers within the cocrystal that are linked by extensive hydrogen bonding [55]. While excess amounts of nicotinamide serve to enhance the solubility of ethyl paraben somewhat, the cocrystal exhibits lower solubility in water with respect to the reactant species, and will precipitate from aqueous solutions at ambient temperature. 

Figure 17 Hydrogen-bonded tapes comprised of cationic [Pt(nicotinamide)4]2+, with chloride ions in channels between tapes. (Reprinted from J. C. Mareque Rivas and L. Brammer, New J. Chem., 22, 1315-8 (1998). Reproduced by permission of the Royal Society of Chemistry (RSC) and the Centre National de la Recherche Scientifique (CNRS).

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