Improving the Water-Solubility of Compounds by Molecular Modification to Disrupt Crystal Packing

Ishikawa, Minoru; Hashimoto, Yuichi

doi:10.1016/b978-0-12-417205-0.00031-6

Cited by 11 publications

(3 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Among those compounds with the best AOX profile, derivatives 18, 20, and 21 showed the best solubility behavior, while compounds 9, 11, and 13 were more insoluble in this aqueous media. It is worthwhile highlighting that as a general trend, the introduction of the methyl group at position N1 increased the solubility of the resulting methylated derivatives (19 >18; 16 >15; 14 >13; 12 >11; 10 >9; 8 >7; 6 >5; 4 >3) in perfect agreement with the variations in the melting points observed (Table 3), which may indicate that there is a distortion in the crystal lattice or in the hydrogen bond network after N-methylation with a reduction in the crystal energy packing [109,110]. On the other hand, the introduction of fluorine atoms in the aromatic ring of the 1,5-benzodiazepin-2(3H)-ones reduced the solubility as can be seen in those fluoroderivatives of compound 18 (18 >17 = 9 >11 = 13 >15).…”

Section: Determination Of Kinetic Solubilitysupporting

confidence: 72%

1,5-Benzodiazepin-2(3H)-ones: In Vitro Evaluation as Antiparkinsonian Agents

et al. 2021

View full text Add to dashboard Cite

A new series of twenty-three 1,5-benzodiazepin-2(3H)-ones were synthesized and evaluated in the 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS), ferric reducing antioxidant power (FRAP), and 2,2-diphenyl-1-picrylhydrazyl (DPPH) assays as a new chemotype with antioxidant and good drug-like properties. All of the derivatives showed low cytotoxicity in comparison to curcumin against the human neuroblastoma SH-SY5Y and the human hepatoma HepG2 cell lines. Experimental solubility in bio-relevant media showed a good relationship with melting points in this series. Five compounds with the best antioxidant properties showed neuroprotectant activity against H2O2-induced oxidative stress in the SH-SY5Y cell line. From them, derivatives 4-phenyl-1H-1,5-benzodiazepin-2(3H)-one (18) and 4-(3,4,5-trimethoxyphenyl)-1H-1,5-benzodiazepin-2(3H)-one (20) yielded good neuroprotection activity in the same neuronal cell line under 6-OHD and MPP+ insults as in vitro models of mitochondrial dysfunction and oxidative stress in Parkinson’s disease (PD). Both compounds also demonstrated a significant reduction of intracellular Reactive Oxygen Species (ROS) and superoxide levels, in parallel with a good improvement of the Mitochondrial Membrane Potential (ΔΨm). Compared with curcumin, compound 18 better reduced lipid peroxidation levels, malondialdehyde (MDA), in SH-SY5Y cells under oxidative stress pressure and recovered intracellular glutathione synthetase (GSH) levels. Apoptosis and caspase-3 levels of SH-SY5Y under H2O2 pressure were also reduced after treatment with 18. Neuroprotection in neuron-like differentiated SH-SY5Y cells was also achieved with 18. In summary, this family of 1,5-benzodiazepin-2-ones with an interesting antioxidant and drug-like profile, with low cytotoxic and good neuroprotectant activity, constitutes a new promising chemical class with high potential for the development of new therapeutic agents against PD.

show abstract

Section: Determination Of Kinetic Solubilitysupporting

confidence: 72%

1,5-Benzodiazepin-2(3H)-ones: In Vitro Evaluation as Antiparkinsonian Agents

et al. 2021

View full text Add to dashboard Cite

show abstract

“…For example, the conformational effect produced by methylation at the R1 and R2 positions of 3 was remarkable, as can be seen by comparing the methylated derivatives (5 and 6) and their unmethylated analogs (4 and 7), which presented more than a 10fold decrease in potency. Moreover, the methylation effect at the 4,6-dimethylpyridone moiety was investigated (9), showing significant differences in potency (10)(11)(12)(13), and the dimethylated compound 10 was the most potent. Subsequently, these important studies regarding the methylation pattern of this system resulted in the discovery of the drug tazemetostat (8) [16].…”

Section: The Discovery Of the Anticancer Drug Tazemetostatmentioning

confidence: 99%

“…Other drug design strategies, such as bioisosterism [ 6 , 7 , 8 ] and homologation [ 9 ], can also benefit from methyl group insertion. During the drug discovery process, controlling conformational behavior can not only favor the adoption of a bioactive conformation, generating a potency gain for pharmacological target modulation, but can also help break to planarity and symmetry, resulting in increased aqueous solubility while increasing lipophilicity [ 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

The Magic Methyl and Its Tricks in Drug Discovery and Development

2023

View full text Add to dashboard Cite

One of the key scientific aspects of small-molecule drug discovery and development is the analysis of the relationship between its chemical structure and biological activity. Understanding the effects that lead to significant changes in biological activity is of paramount importance for the rational design and optimization of bioactive molecules. The “methylation effect”, or the “magic methyl” effect, is a factor that stands out due to the number of examples that demonstrate profound changes in either pharmacodynamic or pharmacokinetic properties. In many cases, this has been carried out rationally, but in others it has been the product of serendipitous observations. This paper summarizes recent examples that provide an overview of the current state of the art and contribute to a better understanding of the methylation effect in bioactive small-molecule drug candidates.

show abstract

Improvement in Aqueous Solubility of Retinoic Acid Receptor (RAR) Agonists by Bending the Molecular Structure

Hiramatsu

Ichikawa

Tomoshige

et al. 2016

Chemistry An Asian Journal

Self Cite

View full text Add to dashboard Cite

Aqueous solubility is a key requirement for many functional molecules, e. g., drug candidates. Decrease of the partition coefficient (log P) by chemical modification, i.e., introduction of hydrophilic group(s) into molecules, is a classical strategy for improving aqueous solubility. We have been investigating alternative strategies for improving the aqueous solubility of pharmaceutical compounds by disrupting intermolecular interactions. Here, we show that introducing a bend into the molecular structure of retinoic acid receptor (RAR) agonists by changing the substitution pattern from para to meta or ortho dramatically enhances aqueous solubility by up to 890-fold. We found that meta analogs exhibit similar hydrophobicity to the parent para compound, and have lower melting points, supporting the idea that the increase of aqueous solubility was due to decreased intermolecular interactions in the solid state as a result of the structural changes.

show abstract

Improving the Water-Solubility of Compounds by Molecular Modification to Disrupt Crystal Packing

Cited by 11 publications

References 43 publications

1,5-Benzodiazepin-2(3H)-ones: In Vitro Evaluation as Antiparkinsonian Agents

1,5-Benzodiazepin-2(3H)-ones: In Vitro Evaluation as Antiparkinsonian Agents

The Magic Methyl and Its Tricks in Drug Discovery and Development

Improvement in Aqueous Solubility of Retinoic Acid Receptor (RAR) Agonists by Bending the Molecular Structure

Contact Info

Product

Resources

About