Supramolecular structure, in vivo biological activities and molecular-docking-based potential cardiotoxic exploration of aconine hydrochloride monohydrate as a novel salt form

Abstract

Despite the high profile of aconine in WuTou injection, there has been no preparative technology or structural studies of its salt as the pharmaceutical product. The lack of any halide salt forms is surprising as aconine contains a tertiary nitrogen atom. In this work, aconine was prepared from the degradation of aconitine in Aconiti kusnezoffii radix (CaoWu). A green chemistry technique was applied to enrich the lipophilic‐poor aconine. Reaction of aconine with hydrochloride acid resulted in protonation of the nitrogen atom and gave a novel salt form (C25H42NO9+·Cl−·H2O; aconine hydrochloride monohydrate, AHM), whose cation in the crystal structure was elucidated based on extensive spectroscopic and X‐ray crystallographic analyses. The AHM crystal had a Z′ = 3 structure with three independent cation–anion pairs, with profound conformational differences among the aconine cations. The central framework of each aconine cation was compared with that of previously reported aconitine, proving that protonation of the nitrogen atom induced the structure rearrangement. In the crystal of AHM, aconine cations, chloride anions and water molecules interacted through inter‐species O—H…Cl and O—H…O hydrogen bonds; this complex hydrogen‐bonding network stabilizes the supramolecular structure. The seriously disordered solvent molecules were treated using the PLATON SQUEEZE procedure [Spek (2015). Acta Cryst. C71, 9–18] and their atoms were therefore omitted from the refinement. Bioactivity studies indicated that AHM promoted in vitro proliferative activities of RAW264.7 cells. Molecular docking suggested AHM could target cardiotoxic protein through the hydrogen‐bonding interactions. The structural confirmation of AHM offers a rational approach for improving the pharmaceutical technology of WuTou injection.

Molecular Insights into Water–Chloride and Water–Water Interactions in the Supramolecular Architecture of Aconine Hydrochloride Dihydrate

“…The hydrogen bonding interactions O6–H6D···Cl1, O5–H5 D ···Cl1 vi , O6–H6 E ···O3, O3–H3 B ···O9 B i and O9 B –H9 B ···O5 contribute to the formation of cyclic motif of S (1); the hydrogen bonding interactions O3–H3 B ···O9 B i , O3–H3 A ···O4 v and O4–H4 D ···O5 B viii contribute to the formation of cyclic motif of S (2); the hydrogen bonding interactions O8 B –H8 B ···O5 and O9 B –H9 B ···O5 contribute to the formation of cyclic motif of S (3). Notably, this type of one-dimensional hydrogen bonding chain is absent in the AHM crystal structure . In addition, the O5B atom in the MB cation accepts an H21F atom in the MC cation (Figure S2 and Table ), forming an intermolecular C21 C –H21 F ···O5 B hydrogen bond that facilitates interactions between supramolecular architectures of MA/MB (Figure a) and MC/MC (Figure b).…”

“…Likewise, the Cl3 anion and H 2 O1 water molecule act as connecting hubs through their interactions with MC cations, resulting in three-dimensional hydrogen bonding networks that contribute to the supramolecular architecture of MC to MC (MC/MC) (Figure b). Comparable supramolecular architectures can be observed in the crystal structure of AHM …”

“…Consequently, the Cl anions do not participate in the formation of intermolecular N + −H•••Cl − hydrogen bonds in MA, MB, and MC cations, which is consistent with previous findings for AHM. 22 Conversely, in another instance of albendazole hydrochloride 33 without water molecules present in its crystal structure, the Cl anions are involved in the The aconine cation structure in AHD is superimposed onto that of lappaconitine, a nonaddictive analgesic used in China for various psychological and chronic pain conditions. 34 It has been found that the central framework of the aconine cation is identical to that of the lappaconitine cation in lappaconitine hydrobromide monohydrate (CCDC accession 241693).…”

“…Comparable supramolecular architectures can be observed in the crystal structure of AHM. 22 The hydroxyl group H8B−O8B serves as a bridge, 37 connecting Cl1 anion and H 2 O5 water with three waters (H 2 O4, H 2 O3, and H 2 O6) to form a one-dimensional hydrogen bonding chain (Figure 4c and Table 3). This chain establishes interactions among supramolecular architectures of MA/MB.…”

“…However, accurate determination of the crystal's composition poses challenges due to the presence of severely disordered waters in the AHM crystal. 22 In this study, we investigate the solid-state landscape of aconine hydrochloride dihydrate (AHD), which represents a new crystalline form of aconine hydrochloride incorporating six water molecules within its asymmetric unit. The complete crystal structure was determined at 136 K using single-crystal X-ray diffraction and refined with SHELXL-IAM, MoPro-IAM, and MoPro-ELMAM2 methods.…”