Structure-based design and synthesis of new 4-methylcoumarin-based lignans as pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β) inhibitors

• Published in: Bioorganic chemistry 2019-08, Vol.89, p.102991, Article 102991
• Main Authors: Santhosh Kumar, S., Sajeli Begum, Ahil, Hira, Kirti, Niazi, Sarfaraj, Prashantha Kumar, B.R., Araya, Hiroshi, Fujimoto, Yoshinori
• Format: Article
• Language: English
• Subjects: Caspase 1; Cinnamate; Cleomiscosin A; Docking; Fused-cyclic coumarin-based lignans; GSF; IL-1β; IL-6; Methylcoumarin; NFκB; Pro-inflammatory cytokine inhibitors; TNF-α
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2019.102991

[Display omitted] •Inhibition of TNF-α, IL-1β and IL-6 by dihydroxymethyl coumarin and ethyl cinnamates.•Design and docking (GOLD) of analogs of above compounds and their fused derivatives (FCLs) over TNF-α, IL-1β & IL-6.•High GOLDScore-fitness and distinctive binding interactions by FCL than standards.•Representative FCLs were synthesized, proved as significant pan-cytokine inhibitors acting through NFκB and caspase 1.•Docking interactions of natural cleomiscosin A and its glycoside were also studied. Suppression of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) along with nitric oxide reduction in RAW 264.7 cells by 7,8-dihydroxy-4-methylcoumarin, ethyl p-coumarate, ethyl caffeate and ethyl ferulate drove us to search structural-analogues of the aforementioned compounds through structure-based drug design. Docking studies revealed that substituted cinnamic acids and their ethyl esters (2-7c) showed higher GoldScore-fitness (GSF) and non-bonding interactions with target proteins than 7,8-dihydroxy-4-methylcoumarin (1a) and 7,8-dihydroxy-5-methylcoumarin (1b). With this background, the methylcoumarins (1a and 1b) and the cinnamic acid derivatives (2-7c) were fused in different permutations and combinations to generate sixty novel fused-cyclic coumarinolignans (FCLs) (8–13k). Docking studies on 8–13k indicated that several FCLs possess higher GSF, interesting active site interactions and distinctive π-π interactions compared to the standards (cleomiscosin A, diclofenac Na and prednisolone). Based on these findings, four novel FCLs (9d, 10d, 11d and 11e) were synthesized and tested for inhibition effect on TNF-α, IL-1β and IL-6 expressions in LPS and oxalate crystal-induced in-vitro models. Compound 10d exhibited significant effect (P