Synthesis of Michael Adducts as Key Building Blocks for Potential Analgesic Drugs: In vitro, in vivo and in silico Explorations

Abstract

Background

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

Acknowledgment

The authors are thankful to the Najran University, Ministry of Education, Kingdom of Saudi Arabia for extending their support in completion of the project (Project No. NU/MID/17/046). We are thankful to the Higher Education Commission of Pakistan for financial support (10562/KPK/NRPU/R&D/2017). Dr. Umer Rashid is thankful to the Higher Education Commission for financial support for the purchase of MOE license under HEC-NRPU project 5291/Federal/NRPU/R&D/HEC/2016.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare that they have no competing interest.