4-Methylcinnamic acid

Probing the Crystal Structure Landscape by Doping: 4-Bromo, 4-Chloro, and 4-Methylcinnamic Acids.[Pubmed:29893027]

Angew Chem Int Ed Engl. 2018 Jul 20;57(30):9279-9283.

Accessing the data points in the crystal structure landscape of a molecule is a challenging task, either experimentally or computationally. We have charted the crystal structure landscape of 4-bromocinnamic acid (4BCA) experimentally and computationally: experimental doping is achieved with 4-Methylcinnamic acid (4MCA) to obtain new crystal structures; computational doping is performed with 4-chlorocinnamic acid (4CCA) as a model system, because of the difficulties associated in parameterizing the Br atom. The landscape of 4CCA is explored experimentally in turn, also by doping it with 4MCA, and is found to bear a close resemblance to the landscape of 4BCA, justifying the ready miscibility of these two halogenated cinnamic acids to form solid solutions without any change in crystal structure. In effect, 4MCA, 4CCA and 4BCA form a commutable group of crystal structures, which may be realized experimentally or computationally, and constitute the landscape. Unlike the results obtained by Kitaigorodskii, all but two of the multiple solid solutions obtained in the methyl-doping experiments take structures that are different from the hitherto observed crystal forms of the parent compounds. Even granted that the latter might be inherently polymorphic, this unusual observation provokes the suggestion that solid solution formation may be used to probe the crystal structure landscape. The influence of pipi interactions, weak hydrogen bonds and halogen bonds in directing the formation of these new structures is also seen.

Cinnamic Acid Analogs as Intervention Catalysts for Overcoming Antifungal Tolerance.[Pubmed:29065462]

Molecules. 2017 Oct 21;22(10). pii: molecules22101783.

Disruption of fungal cell wall should be an effective intervention strategy. However, the cell wall-disrupting echinocandin drugs, such as caspofungin (CAS), cannot exterminate filamentous fungal pathogens during treatment. For potency improvement of cell wall-disrupting agents (CAS, octyl gallate (OG)), antifungal efficacy of thirty-three cinnamic acid derivatives was investigated against Saccharomyces cerevisiaeslt2Delta, bck1Delta, mutants of the mitogen-activated protein kinase (MAPK), and MAPK kinase kinase, respectively, in cell wall integrity system, and glr1Delta, mutant of CAS-responsive glutathione reductase. Cell wall mutants were highly susceptible to four cinnamic acids (4-chloro-alpha-methyl-, 4-methoxy-, 4-methyl-, 3-methylcinnamic acids), where 4-chloro-alpha-methyl- and 4-Methylcinnamic acids possessed the highest activity. Structure-activity relationship revealed that 4-Methylcinnamic acid, the deoxygenated structure of 4-methoxycinnamic acid, overcame tolerance of glr1Delta to 4-methoxycinnamic acid, indicating the significance of para substitution of methyl moiety for effective fungal control. The potential of compounds as chemosensitizers (intervention catalysts) to cell wall disruptants (viz., 4-chloro-alpha-methyl- or 4-Methylcinnamic acids + CAS or OG) was assessed according to Clinical Laboratory Standards Institute M38-A. Synergistic chemosensitization greatly lowers minimum inhibitory concentrations of the co-administered drug/agents. 4-Chloro-alpha-methylcinnamic acid further overcame fludioxonil tolerance of Aspergillus fumigatus antioxidant MAPK mutants (sakADelta, mpkCDelta). Collectively, 4-chloro-alpha-methyl- and 4-Methylcinnamic acids possess chemosensitizing capability to augment antifungal efficacy of conventional drug/agents, thus could be developed as target-based (i.e., cell wall disruption) intervention catalysts.

Crystal engineering: co-crystals of cinnamic acid derivatives with a pyridyl derivative co-crystallizer.[Pubmed:26830799]

Acta Crystallogr B Struct Sci Cryst Eng Mater. 2016 Feb;72(Pt 1):87-95.

A number of hydrogen-bonded co-crystals, consisting of a cinnamic acid derivative and a pyridyl co-crystallizer, have been synthesized and their properties investigated by X-ray diffraction. Samples were prepared by recrystallization or solvent drop grinding of trans-cinnamic acid (1), 4-Methylcinnamic acid (2), 4-methoxy cinnamic acid (3) or 3,4-methoxy cinnamic acid (4), with 4,4-dipyridyl (A), iso-nicotinamide (B) or nicotinamide (C). The X-ray single-crystal structures of seven novel co-crystals, obtained through recrystallization, are examined and the hydrogen-bonding interactions discussed. Consistent hydrogen-bonding motifs were observed for samples prepared when using 4,4-dipyridyl (A) or iso-nicotinamide (B) as the co-crystallizing agent. Powder X-ray diffraction analysis of the samples prepared by solvent drop grinding suggests the formation of ten co-crystals.