Phthalides: Distribution in Nature, Chemical Reactivity, Synthesis, and Biological Activity

Abstract

Phthalides are a relatively small group of natural compounds confined to several plant families and some genera of fungi and liverworts. They are divided into two structural groups, the monomeric and dimeric phthalides, and known mainly as bioactive constituents of different plant species used traditionally for medicinal purposes in Asia, Europe, and North America.The first reports on the chemistry of phthalides appeared at the end of the nineteenth century, in which they were identified as the odor constituents of the essential oil of celery (Apium graveolens) by Ciamician and Silber (1897). In the first half of the last century, phthalides were isolated from Cnidium officinale and Ligusticum acutilobum, species widely used in Asian traditional medicine, and from Levisticum officinale, a species used as food and condiment. Throughout the second part of the twentieth century, phthalides have been characterized from several plant families, namely Asteraceae, Leguminosae, Orchidaceae and Rutaceae, among others, but mainly from the Umbelliferae (syn Apiaceae) family, and the major contributors have been the following species used in traditional medicine: Ligusticum chuanxiong (Chinese name: Chuanxiong), Angelica sinensis (Chinese name: Danggui), Cnidium officinale (Japanese name: Senkyu), Angelica acutiloba (Japanese name: Toki), and Ligusticum porteri (Hispanic name: Oshá). Phthalides are also constituents of several genera of fungi, such as Penicillium, Alternaria and Pestalotiopsis, and some liverworts.Different chromatographic, spectrometric, and two-dimensional nuclear magnetic resonance (NMR) techniques have been used for the isolation and structural characterization of phthalides in extracts, and for assessing the quality of plant material containing this type of compound. Isotopic labeling has established the biosynthesis of phthalides via linkage of acetate units forming polyketide intermediates.Chemical transformations of monomeric phthalides have included oxidation, reduction, addition, elimination, and cycloaddition reactions, and treatments with Lewis acids of (Z)-ligustilide have afforded linear dimers. Some intramolecular condensations and differentiated cyclizations of the dimeric phthalides have been carried out, providing evidences for the particular chemical reactivity of these compounds.Several structural modifications of phthalides have been carried out subjecting them to microbial transformations by different species of bacteria, fungi and algae, and these included resolutions of racemic mixtures and oxidations, among others.The [π4s + π2s] and [π2s + π2s] cycloadditions of (Z)-ligustilide for the synthesis of dimeric phthalides have been reported, and different approaches involving cyclizations, Alder-Rickert reactions, Sharpless asymmetric hydroxylations, or Grignard additions have been used for the synthesis of monomeric phthalides. The use of phthalides as building blocks for divergent oriented synthesis has been proven.Many of the naturally occurring phthalides display different biological...

Synthesis, Bioevaluation, Structure-Activity Relationship and Docking Studies of Natural Product Inspired (Z)-3-benzylideneisobenzofuran-1(3H)-ones as Highly Potent antioxidants and Antiplatelet agents

“…In parallel, further developments were noticed when compounds 28m-q having electron-donating group (EDG) i.e., methyl groups at C-6 position of site I along with H/CH 3 /Cl/OMe groups at p-/m-position of site II were analyzed (Table 1, entry [13][14][15][16][17]. Compound 28m (IC 50 = 7.23 ± 0.04 μg/mL), electron-donating group (CH 3 group) at C-6 position of site I and no substitution at site II, displayed potential activity than ascorbic acid and showed greater activity than that of 28a (Table 1, Entry13).…”

“…Similarly, we analyzed the effect of EDG group at site I and prepared 28m-q having H/CH 3 /Cl/OMe groups at p-/m-position of site II (Table 1, entry [13][14][15][16][17]. Introduction of CH 3 group at site I (28m) showed more aggregation inhibitory activity (IC 50 = 47.93 ± 0.44 μg/mL) than 28a and less activity than 28g (Table 1, entry 13).…”

“…Introduction of CH 3 group at site I (28m) showed more aggregation inhibitory activity (IC 50 = 47.93 ± 0.44 μg/mL) than 28a and less activity than 28g (Table 1, entry 13). The activity has been found comparable to aspirin if CH 3 /Cl substitutions on site II were also introduced ( [16][17]. Sequentially, (EWG) group i.e., fluoro groups at C-6 position of site I were also analyzed (28r-s) and it was observed that both the compounds, 28r (IC 50 = 11.37 ± 0.67 μg/mL) and 28s (IC 50 = 3.25 ± 0.18 μg/mL), exhibited ~two-to seven-folds more potency than aspirin, respectively ( Table 1.…”

“…Synthetic/naturally isolated isobenzofuran-1(3H)-ones and its derivatives have attracted medicinal chemists and pharmacologists due to their pronounced biological activities and their potential applications as antioxidant as well as antiplatelet agents [15][16][17][18][19][20][21] . For example, ascorbic acid 1 15 , Pestacin 17 17 , Micromeriol 18 22 , Pulvinate analogue 19 23 , 5-(bis(3,4-dimethoxyphenyl)-methylene)furan-2(5H)-one 20 24 , ailanthoidol 21 25 , etc.…”

Gut Bacteria of Water Monitor Lizard (Varanus salvator) Are a Potential Source of Antibacterial Compound(s)

“…For example, compounds1,4,5,8,12,13,22,27,33,34,38,39, 49, 51 and 53 were shown to have antibacterial properties against Gram-positive and Gram-negative bacteria including Mycobacterium smegmatis, M. avium, Micrococcus luteus, Enterococcus faecalis, S. aureus and S. epidermidis, E. faecium, B. subtilis, P. aeruginosa, E. coli, P. reinekei and H. pylori. Compounds 3, 16 and 39 were shown to possess anti-inflammatory activity[14][15][16][17][18][19][20][21][22].Compounds 11,13,36,39, 48 and 54 possess antifungal activity where compounds 15 and 16 possess anti-oxidant activities[23][24][25][26][27]. Moreover, there was no biological activity reported for compounds2, 3, 7, 9, 26, 28, 29, 40, 42 and 47.…”