Abstract
A new bisbenzylisoquinoline named as chondrofolinol (1) and four reported compounds (2–5) were isolated and characterized from the roots of Berberis glaucocarpa Stapf. Anti-inflammatory, anti-pyretic, and leishmanicidal studies were performed against carrageenan-induced paw edema, yeast-induced pyrexia, and the promastigotes of Leishmania tropica, respectively. The new compound significantly reduced the paw volume in carrageenan-induced paw edema and rectal temperature in yeast-induced pyrexia at 10 and 20 mg/ kg of body weight. Chondrofolinol caused almost 100% inhibition of the promastigotes of Leishmania tropica. All the compounds displayed minimal cytotoxicity against THP-1 monocytic cells. In order to ascertain the potential macromolecular targets of chondrofolinol responsible for the observed anti-inflammatory and anti-leishmanial activities, a molecular docking study was carried out on relevant protein targets of inflammation and Leishmania. Protein targets of human endoplasmic reticulum aminopeptidase 2 (ERAP2) and human matrix metalloproteinase-1 (MMP-1) for inflammation and protein targets of N-myristoyltransferase (NMT), tyrosyl-tRNA synthetase (TyrRS), and uridine diphosphate-glucose pyrophosphorylase (UGPase) for Leishmania major were selected after thorough literature search about protein targets responsible for inflammation and Leishmania major. Chondrofolinol showed excellent docking to ERAP2 and to MMP-1. The Leishmania major protein targets with the most favorable docking scores to chondrofolinol were NMT, TyrRS, and UGPase. The study indicated that bisbenzylisoquinoline and isoquinoline alkaloids possess anti-pyretic, anti-inflammatory, and anti-leishmanial properties with minimal cytotoxicity and therefore, need to be further explored for their therapeutic potential.
Highlights
Bisbenzylisoquinoline alkaloids contain two benzyl isoquinoline units connected directly through carbon–carbon bond or indirectly through ether or methylenoxy linkages
One new bisbenzylisoquinoline alkaloid named as chondrofolinol (1) and four previously reported compounds (2–5), identified as berberine (2) (Grycova et al, 2007), docosanoic acid (3) (Hsieh et al, 2004), palmatine (4) (Marek et al, 2003), and 8trichloromethyldihydroberberine (5) (Marek et al, 2003), were isolated from the root bark of Berberis glaucocarpa (Figure 1)
The lowest-energy pose of chondrofolinol occupies the active site of the enzyme with key interactions with amino acid residues Gln185, Lys222 (H-bond), Glu40, Gln49 (H-bond), Met149, Phe39, Tyr163 (H-bond), Asp184 (H-bond), and Gly182 (H-bond) (Figure 8)
Summary
Bisbenzylisoquinoline alkaloids contain two benzyl isoquinoline units connected directly through carbon–carbon bond or indirectly through ether or methylenoxy linkages Their structural diversity arises due to variation in the number, position, and nature of ether or carbon–carbon linkages and number of aromatic oxygenated substituents. Pyrexia is body’s natural response to numerous factors including tissue damage, malignancy, cytokinesis, inflammation, and tumor necrosis factor α (TNFα) These conditions trigger the hypothalamus to elevate body temperature (Gupta et al, 2011). Sodium stibogluconate, pentamidine, paramomycin, amphotericin-B, miltefosine, and pentavalent antimony (Grogl et al, 2013) possess several pharmacological drawbacks including prolonged usage, painful administration, toxicity, and resistance by leishmanial parasites These shortcomings necessitate the quest for new potent and safe drugs (Hamill, 2013). Compounds (2–5) from the root bark of Berberis glaucocarpa Stapf along with their in vivo anti-pyretic and anti-inflammatory and in vitro anti-leishmanial properties and molecular docking studies against the abovementioned selected protein targets
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