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

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          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 IC 50 values of 128 and 65 μM with SI of 1.94. Benzyl derivative 11 showed excellent COX-2 inhibition with the IC 50 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.

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          Most cited references 49

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          A new view of pain as a homeostatic emotion.

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          Pain is conventionally viewed as a pattern of convergent activity within the somatosensory system that represents the exteroceptive sense of touch. Accumulating functional, anatomical and imaging findings indicate that pain is generated by specific sensory channels that ascend in a central homeostatic afferent pathway. Phylogenetically new thalamocortical projections in primates provide a sensory image of the physiological condition of the body and, in addition, direct activation of limbic motor cortex. These findings indicate that the human feeling of pain is both a distinct sensation and a motivation - that is, a specific emotion that reflects homeostatic behavioral drive, similar to temperature, itch, hunger and thirst.
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            Therapeutic role of dual inhibitors of 5-LOX and COX, selective and non-selective non-steroidal anti-inflammatory drugs.

            Dual 5-LOX/COX inhibitors are potential new drugs to treat inflammation. They act by blocking the formation of both prostaglandins and leucotrienes but do not affect lipoxin formation. Such combined inhibition avoids some of the disadvantages of selective COX-2 inhibitors and spares the gatrointestinal mucosa.
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              Putting chirality to work: the strategy of chiral switches.

              Most of the new drugs reaching the market today are single enantiomers, rather than the racemic mixtures that dominated up to ten years ago. Many of the new single-enantiomer drugs were developed as such, but there are also important examples of new single-enantiomer drugs derived from 'chiral switches' of established racemates. Indeed, a well-timed chiral switch can offer enhanced therapy and further profitability as a 'line extension' of a major racemic drug with patents that are expiring.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                dddt
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                23 March 2021
                2021
                : 15
                : 1299-1313
                Affiliations
                [1 ]Department of Pharmacy, Faculty of Biological Sciences, University of Malakand , Khyber Pakhtunkhwa, Pakistan
                [2 ]Department of Pharmaceutical Chemistry, College of Pharmacy, Najran University , Najran, Saudi Arabia
                [3 ]Department PCB, Rokhan University , Jalalabad, Nangrahar, Afghanistan
                [4 ]Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus , Abbottabad, 22060, Pakistan
                Author notes
                Correspondence: Abdul Sadiq Department of Pharmacy, Faculty of Biological Sciences, University of Malakand , Chakdara, 18000 Dir (L), Khyber Pakhtunkhwa, PakistanTel +92 301 2297 102 Email sadiquom@yahoo.com
                Umer Rashid Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus , Abbottabad, 22060, PakistanTel +92-334 5171999 Email umerrashid@cuiatd.edu.pk
                Article
                292826
                10.2147/DDDT.S292826
                8001115
                33790541
                © 2021 Ahmad et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 5, Tables: 10, References: 50, Pages: 15
                Categories
                Original Research

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