Abstract
Background: According to the report, in 2022, the prevalence rate of depression in India was 4.50%, and the cases stood at 56,675,969. The development of antidepressant agents has reduced the number of depressant and suicidal cases. Many researchers have found that pyrimidine possesses antidepressant activity. With this background, we thought of synthesizing pyrimidine derivatives.
Objective: The objective of this study is to carry out molecular docking, synthesis, characterization, and evaluation of 2-((4,6-diphenylpyrimidin-2-yl)oxy)-N-phenylacetamide derivatives (17-26) as in vivo antidepressant agent.
Method: The designed compounds were checked for their activity using Molegro virtual docker (MVD) and were further synthesized. Benzaldehyde reacted with acetophenone to give compound (3), which gave compound (4) upon reaction with urea. In another reaction, substituted anilines (5) were reacted with chloroacetyl chloride (6) to yield compounds (7-16), which upon further reaction with compound (4) yielded the final derivatives (17-26). The synthesized compounds were characterized by spectral analysis and checked for their antidepressant activity.
Result: The MolDock scores of the derivatives ranged from -147.097 to −182.095, whereas of active ligand IXX_801 was −115.566. All the synthesized pyrimidine derivatives showed better affinity towards the Cryo-EM structure of the wild-type human serotonin transporter complexed with vilazodone, imipramine, and 15B8 Fab protein (PDB ID: 7LWD) as compared to standard drug clomipramine (−101.064). All the synthesized derivatives were screened for antidepressant activity at a 100mg/kg dose level compared to the standard clomipramine HCl at a dose level of 20mg/kg. Among all the synthesized derivatives, compound 24 showed the most potent antidepressant activity, and Compound 20 showed moderate antidepressant activity, which reduced the duration of immobility times to 35.42% and 31.97% at 100mg/kg dose level when compared to the control, respectively.
Conclusion: Compound 24 showed the highest MolDock score as well as found to be the most potent antidepressant agent.
Graphical Abstract
[1]
Depression and Other Common Mental Disorder. Available from:
https://apps.who.int/iris/bitstream/handle/10665/254610/WHO-MSD-MER-2017.2-eng.pdf (accessed on: 22/11/2022).
[2]
WHO. Mental health:Disorders management. 2012. Available from: https://www.who.int/news-room/fact-sheets/detail/ depressision/?gclid=EAIaIQobChMI8fvsspGGgQMVUg8GAB0v9AN_EAAYASAAEgLgMfD_BwE
[3]
Arya A, Verma P. A Review on pathophysiology, classification and long term course of depression. Int res J pharm 2012; 3: 90-6.
[5]
Shalam MD, Shantakumar SM, Narasu ML. Pharmacologicaland biochemical evidence for the antidepressant effect of the herbal preparation Trans-01. Indian J Pharmacol 2007; 39: 231-4.
[http://dx.doi.org/10.4103/0253-7613.37273]
[http://dx.doi.org/10.4103/0253-7613.37273]
[6]
Depression in India: The Latest Statistics. Available from:
https://mindvoyage.in/depression-in-india-latest-statistics/#:~:text=According%20to%20a%20report%2C%20in,the%20cases%20stand%20at%2056%2C675%2C969
[7]
World Population Review. Available from:
https:// worldpopulationreview.com/country-rankings/depression-rates-by-country
[10]
Oliver Kappe C. 100 years of the biginelli dihydropyrimidine synthesis. Tetrahedron 1993; 49(32): 6937-63.
[http://dx.doi.org/10.1016/S0040-4020(01)87971-0]
[http://dx.doi.org/10.1016/S0040-4020(01)87971-0]
[11]
Sharma P, Rane N, Gurram VK. Synthesis and QSAR studies of pyrimido[4,5-d]pyrimidine-2,5-dione derivatives as potential antimicrobial agents. Bioorg Med Chem Lett 2004; 14(16): 4185-90.
[http://dx.doi.org/10.1016/j.bmcl.2004.06.014] [PMID: 15261267]
[http://dx.doi.org/10.1016/j.bmcl.2004.06.014] [PMID: 15261267]
[12]
Prakash O, Bhardwaj V, Kumar R, Tyagi P, Aneja KR. Organoiodine (III) mediated synthesis of 3-aryl/hetryl-5,7-dimethyl-1,2,4-triazolo[4,3-a]pyrimidines as antibacterial agents. Eur J Med Chem 2004; 39(12): 1073-7.
[http://dx.doi.org/10.1016/j.ejmech.2004.06.011] [PMID: 15571869]
[http://dx.doi.org/10.1016/j.ejmech.2004.06.011] [PMID: 15571869]
[13]
Botta M, Artico M, Massa S, et al. Synthesis, antimicrobial and antiviral activities of isotrimethoprim and some related derivatives. Eur J Med Chem 1992; 27(3): 251-7.
[http://dx.doi.org/10.1016/0223-5234(92)90009-P]
[http://dx.doi.org/10.1016/0223-5234(92)90009-P]
[14]
Agarwal N, Srivastava P, Raghuwanshi SK, et al. Chloropyrimidines as a new class of antimicrobial agents. Bioorg Med Chem 2002; 10(4): 869-74.
[http://dx.doi.org/10.1016/S0968-0896(01)00374-1] [PMID: 11836092]
[http://dx.doi.org/10.1016/S0968-0896(01)00374-1] [PMID: 11836092]
[15]
Roth B, Rauckman BS. 2,4-Diamino-5-(1,2,3,4-tetrahydro-(substituted or unsubstituted)-6-quinolylmethyl)-pyrimidines, useful as antimicrobials. US Patent 45873411986,
[16]
Marquais-Bienewald S, Holzol W, Preuss A, Mehlin A. Use of substituted 2,4-bis (alkylamino) pyrimidines US Patent0188453A1, 2006.
[17]
Daluge SM, Skonezny P, Roth B, Raukman BS. 2,4-Diamino-5-(substituted) pyrimidine, useful as antimicrobials. US Patent 4590271, 1986.
[18]
Ito S, Masuda K, Kusano S, et al. Pyrimidine derivative, process for preparing same and agricultural or horticultural fungicidal composition containing same. US Patent 4590271, 1991.
[19]
Nakagawa Y, Bobrov S, Semer CR, Kucharek TA, Harmoto M. Fungicidal pyrimidine derivatives. US Patent 6818631B1, 2004.
[20]
Agarwal N, Raghuwanshi SK, Upadhyay DN, Shukla PK, Ram VJ. Suitably functionalised pyrimidines as potential antimycotic agents. Bioorg Med Chem Lett 2000; 10(8): 703-6.
[http://dx.doi.org/10.1016/S0960-894X(00)00091-3] [PMID: 10782668]
[http://dx.doi.org/10.1016/S0960-894X(00)00091-3] [PMID: 10782668]
[21]
Basavaraja HS, Sreenivasa GM, Jayachandran E. Synthesis and biological activity of novel pyrimidino imidazolines. Indian J Heterocycl Chem 2005; 15: 69.
[22]
Ram VJ, Haque N, Guru PY. Chemotherapeutic agents XXV: Synthesis and leishmanicidal activity of carbazolylpyrimidines. Eur J Med Chem 1992; 27(8): 851-5.
[http://dx.doi.org/10.1016/0223-5234(92)90121-G]
[http://dx.doi.org/10.1016/0223-5234(92)90121-G]
[23]
Amir M, Javed SA, Kumar H. Pyrimidine as antiinflammatory agent: A review. Indian J Pharm Sci 2007; 69(3): 337.
[http://dx.doi.org/10.4103/0250-474X.34540]
[http://dx.doi.org/10.4103/0250-474X.34540]
[24]
Sondhi SM, Jain S, Dwivedi AD, Shukla R, Raghubir R. Synthesis of condensed pyrimidines and their evaluation for anti-inflammatory and analgesic activities. Ind J Chemi B 2008; 47(1): 136-43.
[25]
Vega S, Alonso J, Diaz JA, Junquera F. Synthesis of 3-substituted-4-phenyl-2-thioxo-1,2,3,4,5,6,7,8-octahydrobenzo[4,5]thieno[2,3-á]pyrimidines. J Heterocycl Chem 1990; 27(2): 269-73.
[http://dx.doi.org/10.1002/jhet.5570270229]
[http://dx.doi.org/10.1002/jhet.5570270229]
[26]
Hannah DR, Stevens MFG. Structural studies on bioactive compounds—part 38.1: Reactions of 5-aminoimidazole-4-carboxamide: synthesis of imidazo[1,5-a]quinazoline-3-carboxamides. J Chem Res 2003; 2003(7): 398-401.
[http://dx.doi.org/10.3184/030823403103174533]
[http://dx.doi.org/10.3184/030823403103174533]
[27]
Rana K, Kaur B, Kumar B. Synthesis and anti-hypertensive activity of some dihydropyrimidines. Ind J Chem B 2004; 43(7): 1553-7.
[28]
Smith PAS, Kan RO. Cyclization of isothiocyanates as a route to phthalic and homophthalic acid derivatives. J Org Chem 1964; 29(8): 2261-5.
[http://dx.doi.org/10.1021/jo01031a037]
[http://dx.doi.org/10.1021/jo01031a037]
[29]
Balzarini J, McGuigan C. Bicyclic pyrimidine nucleoside analogues (BCNAs) as highly selective and potent inhibitors of varicella-zoster virus replication. J Antimicrob Chemother 2002; 50(1): 5-9.
[http://dx.doi.org/10.1093/jac/dkf037] [PMID: 12096000]
[http://dx.doi.org/10.1093/jac/dkf037] [PMID: 12096000]
[30]
von Borstel RW. Treatment of chemotherapeutic agent and antiviral agent toxicity with acylated pyrimidine nucleosides. US Patent 6344447B2, 2002.
[32]
Lee H, Kim B, Ahn J, et al. Molecular design, synthesis, and hypoglycemic and hypolipidemic activities of novel pyrimidine derivatives having thiazolidinedione. Eur J Med Chem 2005; 40(9): 862-74.
[http://dx.doi.org/10.1016/j.ejmech.2005.03.019] [PMID: 15908051]
[http://dx.doi.org/10.1016/j.ejmech.2005.03.019] [PMID: 15908051]
[33]
Juby PF, Hudyma TW, Brown M, Essery JM, Partyka RA. Antiallergy agents. 1. 1,6-Dihydro-6-oxo-2-phenylpyrimidine-5-carboxylic acids and esters. J Med Chem 1979; 22(3): 263-9.
[http://dx.doi.org/10.1021/jm00189a009] [PMID: 423208]
[http://dx.doi.org/10.1021/jm00189a009] [PMID: 423208]
[34]
Gupta AK, Sanjay HP, Kayath A, Singh G, Sharma KC. Anticonvulsant activity of pyrimidine thiols. Indian J Pharmacol 1994; 26(3): 227-8.
[http://dx.doi.org/10.4103/ijp.IJP_486_20]
[http://dx.doi.org/10.4103/ijp.IJP_486_20]
[35]
Abu-Hashem AA, Youssef MM, Hussein HAR. Synthesis, antioxidant, antituomer activities of some new thiazolopyrimidines, pyrrolothiazolopyrimidines and triazolopyrrolothiazolopyrimidines derivatives. J Chin Chem Soc 2011; 58(1): 41-8.
[http://dx.doi.org/10.1002/jccs.201190056]
[http://dx.doi.org/10.1002/jccs.201190056]
[36]
Abu-Hashem A, El-Shehry M, Badria F. Design and synthesis of novel thiophenecarbohydrazide, thienopyrazole and thienopyrimidine derivatives as antioxidant and antitumor agents. Acta Pharm 2010; 60(3): 311-23.
[http://dx.doi.org/10.2478/v10007-010-0027-6] [PMID: 21134865]
[http://dx.doi.org/10.2478/v10007-010-0027-6] [PMID: 21134865]
[37]
Rahaman SA, Rajendra Pasad Y, Kumar P, Kumar B. Synthesis and anti-histaminic activity of some novel pyrimidines. Saudi Pharm J 2009; 17(3): 255-8.
[http://dx.doi.org/10.1016/j.jsps.2009.08.001] [PMID: 23964169]
[http://dx.doi.org/10.1016/j.jsps.2009.08.001] [PMID: 23964169]
[38]
Nezu Y, Miyazaki M, Sugiyama K, Kajiwara I. Dimethoxypyrimidine as novel herbicides—part 1: Synthesis and herbicidal activity of dimethoxyphenoxyphenoxypyrimidines and analogues. Pestic Sci 1996; 47: 103-13.
[http://dx.doi.org/10.1002/(SICI)1096-9063(199606)47:2<103::AID-PS396>3.0.CO;2-Z]
[http://dx.doi.org/10.1002/(SICI)1096-9063(199606)47:2<103::AID-PS396>3.0.CO;2-Z]
[39]
Coe JW, Fliri AFJ, Kaneko T, Larson ER. Pyrimidine derivatives enhancing antitumour activity. US Patent 5491234, 1996.
[40]
Breault GA, Newcombe NJ, Thomas AP. Imidazolo-5-YL-2-anilino-pyrimidines as agents for the inhibition of the cell proliferation 2005.
[41]
Xie F, Zhao H, Zhao L, Lou L, Hu Y. Synthesis and biological evaluation of novel 2,4,5-substituted pyrimidine derivatives for anticancer activity. Bioorg Med Chem Lett 2009; 19(1): 275-8.
[http://dx.doi.org/10.1016/j.bmcl.2008.09.067] [PMID: 19028425]
[http://dx.doi.org/10.1016/j.bmcl.2008.09.067] [PMID: 19028425]
[42]
Kaldrikyan MA, Grigoryan LA, Geboyan VA, Arsenyan FG, Stepanyan GM, Garibdzhanyan BT. Synthesis and antitumor activity of some disubstituted 5-(3-methyl-4-alkoxybenzyl)pyrimidines. Pharm Chem J 2000; 34(10): 521-4.
[http://dx.doi.org/10.1023/A:1010398911988]
[http://dx.doi.org/10.1023/A:1010398911988]
[43]
Rodrigues ALS, Rosa JM, Gadotti VM, et al. Antidepressant-like and antinociceptive-like actions of 4-(4′-chlorophenyl)-6-(4″-methylphenyl)-2-hydrazinepyrimidine Mannich base in mice. Pharmacol Biochem Behav 2005; 82(1): 156-62.
[http://dx.doi.org/10.1016/j.pbb.2005.08.003] [PMID: 16153700]
[http://dx.doi.org/10.1016/j.pbb.2005.08.003] [PMID: 16153700]
[44]
Tani J, Yamada Y, Oine T, Ochiai T, Ishida R, Inoue I. Studies on biologically active halogenated compounds. 1. Synthesis and central nervous system depressant activity of 2-(fluoromethyl)-3-aryl-4(3H)-quinazolinone derivatives. J Med Chem 1979; 22(1): 95-9.
[http://dx.doi.org/10.1021/jm00187a021] [PMID: 423189]
[http://dx.doi.org/10.1021/jm00187a021] [PMID: 423189]
[45]
Kumar B, Kaur B, Kaur J, Parmar A, Anand RD, Kumar H. Thermal/microwave assisted synthesis of substituted tetrahydropyrimidines as potent calcium channel blockers. ChemInform 2002; 33(43): no.
[http://dx.doi.org/10.1002/chin.200243181]
[http://dx.doi.org/10.1002/chin.200243181]
[46]
Balaji PN, Sreevani MS, Harini P, Rani J, Prathusha K, Chandu TJ. Antimicrobial activity of some heterocyclic compounds from substituted chalcones. J Chem Pharm Res 2010; 2(4): 754-8.
[47]
Elarfi MJ, Al-Difar HA. Synthesis of some heterocyclic compounds derived from chalcones. SciRevsChemCommun 2012; 2(2): 103-7.
[48]
Priolkar RNS, Shingade S, Palkar M. MamleDesai S, MamleDesai S. Design, synthesis and characterisation of novel linomide analogues and their evaluation for anticancer activity. Curr Drug Discov Technol 2020; 16: 1-10.
[49]
Palkar MB, Singhai AS, Ronad PM, et al. Synthesis, pharmacological screening and in silico studies of new class of Diclofenac analogues as a promising anti-inflammatory agents. Bioorg Med Chem 2014; 22(10): 2855-66.
[http://dx.doi.org/10.1016/j.bmc.2014.03.043] [PMID: 24751552]
[http://dx.doi.org/10.1016/j.bmc.2014.03.043] [PMID: 24751552]
[50]
Stamos J, Sliwkowski MX, Eigenbrot C. Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor. J Biol Chem 2002; 277(48): 46265-72.
[http://dx.doi.org/10.1074/jbc.M207135200] [PMID: 12196540]
[http://dx.doi.org/10.1074/jbc.M207135200] [PMID: 12196540]
[51]
Poleszak E, Wośko S, Serefko A, et al. The effects of ifenprodil on the activity of antidepressant drugs in the forced swim test in mice. Pharmacol Rep 2014; 66(6): 1031-6.
[http://dx.doi.org/10.1016/j.pharep.2014.06.016] [PMID: 25443731]
[http://dx.doi.org/10.1016/j.pharep.2014.06.016] [PMID: 25443731]
