DESIGN, IN-SILICO DOCKING AND PREDICTIVE ADME PROPERTIES OF NOVEL PYRAZOLINE DERIVATIVES WITH SELECTIVE HUMAN MAO INHIBITORY ACTIVITY

  • Vishnu Nayak Badavath Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi 835215, Jharkhand, India
  • Barij Nayan Sinha Birla Institute of Technology, Mesra, Ranchi 835215, Jharkhand, India
  • Venkatesan Jayaprakash Birla Institute of Technology, Mesra, Ranchi 835215, Jharkhand, India

Abstract

Objectives: Curcumin, a known hMAO-A (human Monoamine oxidase-A) inhibitor from Curcuma longa has never been recognized for this property due to its poor permeability and extensive metabolism. Thus, the main objective of this study is to incorporate structural features of Curcumin in the pyrazoline scaffold as an attempt to get potent, selective hMAO-isoform inhibitors with improved permeability.

Methods: A series of twelve novel 4, 4'-(4, 5-dihydro-1H-pyrazole-3,5-diyl)bis(2-methoxyphenol) derivatives (1-12) were designed based on the structure of Curcumin. All the designed compounds were evaluated for their hMAO inhibitory activity by in-silico docking studies (Autodock4.20). The both isomers (R-and S-isomer) are considered for simulation approach to understand the effect of chirality and other structural features that determine the potency and selectivity. In order to judge the pharmacokinetic behavior, all the derivatives were evaluated for their in-silico ADME properties by using Qik Prop v 3.0.

Results: The results of the present study showed that all the designed compounds were found to be potent and selective hMAO-isoform inhibitors, and exhibited lead like properties from the calculated ADME parameters. Curcumin was taken as a standard for comparison to judge any improvement in permeability.

Conclusion: The design strategy adopted has predicted improved potency, selective towards hMAO-isoform and permeability characteristics in comparison with Curcumin.

 

Keywords: Pyrazoline, hMAO inhibitors, Molecular docking simulation, Autodock4.20, Pharmacokinetic parameters, Schrodinger LLC, Structure-activity relationship

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Author Biography

Vishnu Nayak Badavath, Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi 835215, Jharkhand, India
Department of Pharmaceutical Science and Technology, Mesra

References

1. Youdim MBH, Collins GGS, Sandler M, Jones ABB, Pare CMB, Nicholson WJ. Biological sciences: human brain monoamine oxidase: multiple forms and selective inhibitors. Nature 1972;236:225–8.
2. Collins GGS, Sandler M, Williams ED, Youdim MBH. Multiple forms of human brain mitochondrial monoamine oxidase. Nature 1970;225:817–20.
3. Johnson JP. Some observations upon a new inhibitor of monoamine oxidase in brain tissue. Biochem Pharmacol 1968;17:1285–97.
4. Knoll J, Magyar K. Some puzzling pharmacological effects of monoamine oxidase inhibitors. Adv Biochem Psychopharmacol 1972;5:393-408.
5. O Carroll AM, Fowler CJ, Phillips JP, Tobbia I, Tipton KF. The deamination of dopamine by human brain monoamine oxidase-Specificity for the two enzyme forms in seven brain regions. Naunyn-Schmiedeberg's Arch Pharmacol 1983;322:198–202.
6. Da Prada M, Keller HH, Kettler R. Comparison of the new MAO-A inhibitors moclobemide, brofaromine and toloxatone with tranylcypromine in an animal experiment: significance for clinical practice. Psychiatr Prax 1989;16(Suppl 1):18–24.
7. Lavian G, Finberg JP, Youdim MB. The advent of a new generation of monoamine oxidase inhibitor antidepressants: pharmacologic studies with moclobemide and brofaromine. Clin Neuropharmacol 1993;16(Suppl 2):S1–7.
8. Youdim MBH, Weinstock M. Therapeutic applications of selective and non-selective inhibitors of monoamine oxidase A and B that do not cause significant tyramine potentiation. Neurotoxicology 2004;25:243–50.
9. Mishra N, Sasmal D. Development of selective and reversible pyrazoline based MAO-B inhibitors: virtual screening, synthesis and biological evaluation. Bioorg. Med Chem Lett 2011;21:1969–73.
10. Mathew B, Suresh J, Anbazhagan S, Elizabeth Mathew G. Pyrazoline: a promising scaffold for the inhibition of monoamine oxidase. Cent Nerv Syst Agents Med Chem 2013;13:195–206.
11. Xu Y, Ku BS, Yao HY, Lin YH, Ma X, Zhang YH, et al. Antidepressant effects of curcumin in the forced swim test and olfactory bulbectomy models of depression in rats. Pharmacol Biochem Behav 2005;82:200–6.
12. Kulkarni SK, Bhutani MK, Bishnoi M. Antidepressant activity of curcumin: Involvement of serotonin and dopamine system. Psychopharmacology 2008;201:435–42.
13. Rajeswari A, Sabesan M. Inhibition of monoamine oxidase-B by the polyphenolic compound, curcumin and its metabolite tetrahydrocurcumin, in a model of Parkinson’s disease induced by MPTP neurodegeneration in mice. Inflammopharmacology 2008;16:96–9.
14. Zhang L, Luo J, Zhang M, Yao W, Ma X, Yu SY. Effects of curcumin on chronic, unpredictable, mild, stress-induced depressive-like behaviour and structural plasticity in the lateral amygdala of rats. Int J Neuropsychopharmacol 2014;17:793–806.
15. Wang R, Xu Y, Wu HL, Li YB, Li YH, Guo JB, et al. The antidepressant effects of curcumin in the forced swimming test involve 5-HT1 and 5-HT2 receptors. Eur J Pharmacol 2008;578:43–50.
16. Xu Y, Ku BS, Yao HY, Lin YH, Ma X, Zhang YH, et al. The effects of curcumin on depressive-like behaviors in mice. Eur J Pharmacol 2005;518:40–6.
17. Tonnesen HH, Masson M, Loftsson T. Studies of curcumin and curcuminoids. XXVII. Cyclodextrin complexation: Solubility, chemical and photochemical stability. Int J Pharm 2002;244:127–35.
18. Wang. YJ, Pan MH, Cheng AL, Lin LI, Ho YS, Hsieh CY, et al. Stability of curcumin in buffer solutions and characterization of its degradation products. J Pharm Biomed Anal 1997;15:1867–76.
19. Mayersohn M, Guentert TW. Clinical pharmacokinetics of the monoamine oxidase-a inhibitor moclobemide. Clin Pharmacokinet 1995;29:292–332.
20. Raaflaub J, Haefelfinger P, Trautmann KH. Single-dose pharmacokinetics of the mao-inhibitor moclobemide in man. Arzneimittelforschung 1984;34:80–2.
21. Nair NPV, Ahmed SK, Ng Ying Kin NMK. Biochemistry and pharmacology of reversible inhibitors of MAO-A agents: focus on moclobemide. J Neuropsychiatry Clin Neurosci 1993;18:214–25.
22. Barrett JS, Szego P, Rohatagi S, Morales RJ, DeWitt KE, Rajewski G, et al. Absorption and presystemic metabolism of selegiline hydrochloride at different regions in the gastrointestinal tract in healthy males. Pharm Res 1996;13:1535–40.
23. Laine K, Anttila M, Helminen A, Karnani H, Huupponen R. Dose linearity study of selegiline pharmacokinetics after oral administration: evidence for strong drug interaction with female sex steroids. Br J Clin Pharmacol 1999;47:249–54.
24. Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, et al. AutoDock4 and AutoDockTools4:Automated docking with selective receptor flexibility. J Comput Chem 2009;30:2785–91.
25. Vishnu Nayak B, Ciftci-Yabanoglu S, Soumendranath B, Ajay K. T, Barij N Sinha, Ucar, G, Mahmoud E S S, Venkatesan J. Monoamine oxidase inhibitory activity of 2-aryl-4H-chromen-4-ones. Bioorg Chem 2015; 58: 72–80.
26. Vishnu Nayak B, Ciftci-Yabanoglu S, Jadav SS, Jagrat M, Sinha BN, Ucar G, et al. Monoamine oxidase inhibitory activity of 3,5-biaryl-4,5-dihydro-1H-pyrazole-1-carboxylate derivatives. Eur J Med Chem 2013;69:762–7.
27. Sahoo A, Yabanoglu S, Sinha BN, Ucar G, Basu A, Jayaprakash V. Towards development of selective and reversible pyrazoline based MAO-inhibitors: Synthesis, biological evaluation and docking studies. Bioorganic Med Chem Lett 2010;20:132–6.
28. Jagrat M, Behera J, Yabanoglu S, Ercan A, Ucar G, Sinha BN, et al. Pyrazoline based MAO inhibitors: synthesis, biological evaluation and SAR studies. Bioorg Med Chem Lett 2011;21:4296–300.
29. Chimenti F, Bolasco A, Manna F, Secci D, Chimenti P, Befani O, et al. Synthesis and selective inhibitory activity of 1-acetyl-3, 5-diphenyl-4, 5-dihydro-(1 H)-pyrazole derivatives against monoamine oxidase. J Med Chem 2004;47:2071–4.
30. Chimenti F, Fioravanti R, Bolasco A, Manna F, Chimenti P, Secci D, et al. Synthesis, molecular modeling studies and selective inhibitory activity against MAO of N1-propanoyl-3,5-diphenyl-4,5-dihydro-(1H)-pyrazole derivatives. Eur J Med Chem 2008;43:2262-7.
31. Schrodinger LLC. Maestro 8.5 user manual; 2008.
32. Debnath B, Ganguly S. Molecular docking studies and ADME prediction of novel Isatin analogs as Hiv-1-Rt inhibitors with broad spectrum chemotherapeutic properties. Asian J Pharm Clin Res 2014;7:186-94.
33. Ganguly S, Debnath B. Molecular docking studies and ADME prediction of novel Isatin analogs with potent anti-EGFR activity. Med Chem 2014;4:558–68.
34. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Delivery Rev 1997;23:3-25.
35. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Delivery Rev 2001;46:3-26.
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How to Cite
Badavath, V. N., B. N. Sinha, and V. Jayaprakash. “DESIGN, IN-SILICO DOCKING AND PREDICTIVE ADME PROPERTIES OF NOVEL PYRAZOLINE DERIVATIVES WITH SELECTIVE HUMAN MAO INHIBITORY ACTIVITY”. International Journal of Pharmacy and Pharmaceutical Sciences, Vol. 7, no. 12, Nov. 2015, pp. 277-82, https://innovareacademics.in/journals/index.php/ijpps/article/view/9212.
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