Synthesis, molecular docking evaluation for LOX and COX-2 inhibition and determination of in-vivo analgesic potentials of aurone derivatives

Muhammad Ikram; Ismail Shah; Haya Hussain; Ehsan Ullah Mughal; Nafeesa Naeem; Amina Sadiq; Yasir Nazir; Syed Wadood Ali Shah; Muhammad Zahoor; Riaz Ullah; Essam A Ali; Muhammad Naveed Umar

doi:10.1016/j.heliyon.2024.e29658

Synthesis, molecular docking evaluation for LOX and COX-2 inhibition and determination of in-vivo analgesic potentials of aurone derivatives

Heliyon. 2024 Apr 20;10(9):e29658. doi: 10.1016/j.heliyon.2024.e29658. eCollection 2024 May 15.

Authors

Affiliations

¹ Department of Pharmacy, Abdul Wali Khan University Mardan (AWKUM), Mardan, 23390, Pakistan.
² Department of Pharmacy, Shaheed Benazir Bhutto University Sheringal, Dir (Upper) 18000, Khyber Pakhtunkhwa, Pakistan.
³ Department of Chemistry, University of Gujrat, Gujrat, 50700, Pakistan.
⁴ Department of Chemistry, Govt. College Women University, Sialkot, 51300, Pakistan.
⁵ Department of Chemistry, University of Sialkot, Sialkot, 51300, Pakistan.
⁶ Department of Pharmacy, University of Malakand, Chakdara, Chakdara 18800, Khyber Pakhtunkhwa, Pakistan.
⁷ Department of Biochemistry, University of Malakand, Chakdara, Dir Lower, KPK, 18800, Pakistan.
⁸ Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
⁹ Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
¹⁰ Department of Chemistry, University of Liverpool, UK.

Abstract

In the current study, seven (7) aurone derivatives (ADs) were synthesized and employed to in-vitro LOX and COX-2 assays, in-vivo models of acetic acid-induced mice writhing, formalin-induced mice paw licking and tail immersion test to evaluate their analgesic potential at the doses of 10 mg and 20 mg/kg body weight. Molecular docking was performed to know the active binding site at both LOX and COX-2 as compared to standard drugs. Among the ADs, 2-(3,4-dimethoxybenzylidene)benzofuran-3(2H)-one (WE-4)possessed optimal LOX and COX-2 inhibitory strength (IC₅₀=0.30 μM and 0.22 μM) as compared to standard (ZileutonIC₅₀ = 0.08 μM, CelecoxibIC₅₀ = 0.05 μM). Similarly in various pain models compound WE-4 showed significantly (p < 0.05) highest percent analgesic potency as compared to control at a dose of 20 mg/kg i.e. 77.60 % analgesic effect in acetic acid model, 49.97 % (in Phase-1) and 70.93 % (inPhase-2) analgesic effect in formalin pain model and 74.71 % analgesic response in tail immersion model. By the administration of Naloxone, the tail flicking latencies were reversed (antagonized) in all treatments. The WE-4 (at 10 mg/kg and 20 mg/kg) was antagonized after 90 min from 11.23 ± 0.93 and 13.41 ± 1.21 to 5.30 ± 0.48 and 4.80 ± 0.61 respectively as compared to standard Tramadol (from 17.74 ± 1.33 to 3.70 ± 0.48), showing the opiodergic receptor involvement. The molecular docking study of ADs revealed that WE-4 had a higher affinity for LOX and COX-2 with docking scores of -4.324 and -5.843 respectively. As a whole, among the tested ADs, compound WE-4 demonstrated excellent analgesic effects that may have been caused by inhibiting the LOX and COX-2 pathways.

Keywords: Analgesic; Aurone derivatives; COX-2; IC50; LOX; Molecular docking; Opioid mechanism.