Drug Design, Development and Therapy (Mar 2021)
Synthesis of Michael Adducts as Key Building Blocks for Potential Analgesic Drugs: In vitro, in vivo and in silico Explorations
Abstract
Sajjad Ahmad,1 Mater H Mahnashi,2 Bandar A Alyami,2 Yahya S Alqahtani,2 Farhat Ullah,1 Muhammad Ayaz,1 Muhammad Tariq,3 Abdul Sadiq,1 Umer Rashid4 1Department of Pharmacy, Faculty of Biological Sciences, University of Malakand, Khyber Pakhtunkhwa, Pakistan; 2Department of Pharmaceutical Chemistry, College of Pharmacy, Najran University, Najran, Saudi Arabia; 3Department PCB, Rokhan University, Jalalabad, Nangrahar, Afghanistan; 4Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, Abbottabad, 22060, PakistanCorrespondence: Abdul SadiqDepartment of Pharmacy, Faculty of Biological Sciences, University of Malakand, Chakdara, 18000 Dir (L), Khyber Pakhtunkhwa, PakistanTel +92 301 2297 102Email [email protected] RashidDepartment of Chemistry, COMSATS University Islamabad, Abbottabad Campus, Abbottabad, 22060, PakistanTel +92-334 5171999Email [email protected]: Organocatalytic asymmetric Michael addition is a strong approach for C-C bond formation. The objective of the study is to design molecules by exploiting the efficiency of Michael Adducts. We proceeded with the synthesis of Michael adducts by tailoring the substitution pattern on maleimide and trans-β-nitro styrene as Michael acceptors. The synthesized compounds were evaluated for dual cyclooxygenases (COX) and lipoxygenase (LOX) inhibition.Methods: The compounds (4, 9– 11) were synthesized through Michael additions. The cyclooxygenases (COX-1 and 2) and lipoxygenase (5-LOX) assays were used for in vitro evaluations of compounds. After the acute toxicity studies, the in vivo analgesic potential was determined with acetic acid induced writhing, tail immersion, and formalin tests. Furthermore, the possible roles of adrenergic and dopaminergic receptors were also studied. Extensive computational studies were performed to get a better understanding regarding the binding of this compound with protein target.Results: Four Michael adducts (4, 9– 11) were synthesized. Compound 4 was obtained in enantio- and diastereopure form. The stereopure compound 4 showed encouraging COX-1 and-2 inhibitions with IC50 values of 128 and 65 μM with SI of 1.94. Benzyl derivative 11 showed excellent COX-2 inhibition with the IC50 value of 5.79 μM and SI value 7.96. Compounds 4 and 11 showed good results in in vivo models of analgesia like acetic acid test, tail immersion, and formalin tests. Our compounds were not active in dopaminergic and adrenergic pathways and so were acting centrally. Through extensive computational studies, we computed binding energies, and pharmacokinetic predictions.Conclusion: Our findings conclude that our synthesized Michael products (pyrrolidinedione 4 and nitroalkane 11) can be potent centrally acting analgesics. Our in silico predictions suggested that the compounds have excellent pharmacokinetic properties. It is concluded here that dual inhibition of COX/LOX pathways provides a convincing step towards the discovery of safe lead analgesic molecules.Keywords: Michael products, succinimides, cyclooxygenase, lipoxygenase, analgesic, molecular docking, adrenergic and dopaminergic
