Abstract
Background: Several studies have been conducted on 4-H chromene compounds because of their intriguing pharmacological and biological properties. Various new natural compounds having a chromene foundation have been reported over the past 20 years.
Objective: In the present study, we reported the acute oral toxicity, antioxidant activity, and molecular docking study of the most active 4H-chromene derivative2-(4-Bromo-phenoxy)-N-[6-chloro-4-(4- chlorophenyl)-3-cyano-4H-chromen-2-yl]-acetamide (A9).
Method: The acute oral toxicity was carried out as per OECD 423 guidelines. For investigating the antioxidant activity, various biochemical parameters in colon tissue like SOD, CAT, MDA, PC and GSH and also enzyme levels, such as ALT, AST, ALP, and LDH, were measured in this experiment.
Results: Acute oral toxicity study indicated that the A9 ligand was found to be safer in animals. Additionally, the A9 ligand had significant antioxidant properties at various doses and was not found to be harmful to the liver. Due to its stronger binding energy and the appropriate interactions that induce inhibition, the A9 ligand's antioxidant function was also validated by additional molecular docking research.
Conclusion: This compound can be exploited as a lead molecule in further research.
Graphical Abstract
[1]
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68(6): 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[2]
de Mesquita ML, Araújo RM, Bezerra DP, et al. Cytotoxicity of δ-tocotrienols from Kielmeyera coriacea against cancer cell lines. Bioorg Med Chem 2011; 19(1): 623-30.
[http://dx.doi.org/10.1016/j.bmc.2010.10.044] [PMID: 21094611]
[http://dx.doi.org/10.1016/j.bmc.2010.10.044] [PMID: 21094611]
[3]
Noushini1 S, Alipour1 E, Emami S. Synthesis and cytotoxic properties of novel (E)-3-benzylidene-7- methoxychroman-4-one Derivatives. DARU J Pharmaceut Sci 2013; 21: 31.
[4]
Colombano G, Travelli C, Galli U, et al. A novel potent nicotinamide phosphoribosyltransferase inhibitor synthesized via click chemistry. J Med Chem 2010; 53(2): 616-23.
[http://dx.doi.org/10.1021/jm9010669] [PMID: 19961183]
[http://dx.doi.org/10.1021/jm9010669] [PMID: 19961183]
[5]
Costa M, Dias TA, Brito A, Proença F. Biological importance of structurally diversified chromenes. Eur J Med Chem 2016; 123: 487-507.
[http://dx.doi.org/10.1016/j.ejmech.2016.07.057] [PMID: 27494166]
[http://dx.doi.org/10.1016/j.ejmech.2016.07.057] [PMID: 27494166]
[6]
Puppala M, Zhao X, Casemore D, et al. 4H-Chromene-based anticancer agents towards multi-drug resistant HL60/MX2 human leukemia: SAR at the 4th and 6th positions. Bioorg Med Chem 2016; 24(6): 1292-7.
[http://dx.doi.org/10.1016/j.bmc.2016.01.056] [PMID: 26867486]
[http://dx.doi.org/10.1016/j.bmc.2016.01.056] [PMID: 26867486]
[7]
Rehse K, Schinkel W. Anticoagulante 3-Aralkyl-4-hydroxy-2-pyrone. Arch Pharm (Weinheim) 1983; 316(12): 988-94.
[http://dx.doi.org/10.1002/ardp.19833161204] [PMID: 6661006]
[http://dx.doi.org/10.1002/ardp.19833161204] [PMID: 6661006]
[8]
Shah NK, Shah NM, Patel MP, Patel RG. Synthesis of 2-amino-4H-chromene derivatives under microwave irradiation and their antimicrobial activity. J Chem Sci 2013; 125(3): 525-30.
[http://dx.doi.org/10.1007/s12039-013-0421-y]
[http://dx.doi.org/10.1007/s12039-013-0421-y]
[9]
Fatima I, Saxena R, Kharkwal G, et al. The anti-proliferative effect of 2-[piperidinoethoxyphenyl]-3-[4-hydroxyphenyl]-2H-benzo(b) pyran is potentiated via induction of estrogen receptor beta and p21 in human endometrial adenocarcinoma cells. J Steroid Biochem Mol Biol 2013; 138: 123-31.
[http://dx.doi.org/10.1016/j.jsbmb.2013.04.005] [PMID: 23688837]
[http://dx.doi.org/10.1016/j.jsbmb.2013.04.005] [PMID: 23688837]
[10]
Gregor W, Grabner G, Adelwöhrer C, Rosenau T, Gille L. Antioxidant properties of natural and synthetic chromanol derivatives: study by fast kinetics and electron spin resonance spectroscopy. J Org Chem 2005; 70(9): 3472-83.
[http://dx.doi.org/10.1021/jo047927s] [PMID: 15844980]
[http://dx.doi.org/10.1021/jo047927s] [PMID: 15844980]
[11]
Boukattaya F, Daoud A, Boeda F, et al. Synthesis and biological evaluation of 3-cyano-4h-chromene derivatives bearing carbamate functionality. Med Chem 2019; 15(3): 257-64.
[http://dx.doi.org/10.2174/1573406414666181009124449] [PMID: 30306877]
[http://dx.doi.org/10.2174/1573406414666181009124449] [PMID: 30306877]
[12]
Carr M, Knox AJS, Nevin DK, et al. Optimisation of estrogen receptor subtype-selectivity of a 4-Aryl-4H-chromene scaffold previously identified by virtual screening. Bioorg Med Chem 2020; 28(5): 115261.
[http://dx.doi.org/10.1016/j.bmc.2019.115261] [PMID: 31987694]
[http://dx.doi.org/10.1016/j.bmc.2019.115261] [PMID: 31987694]
[13]
Conti C, Proietti Monaco L, Desideri N. Synthesis and anti-rhinovirus activity of novel 3-[2-(pyridinyl)vinyl]substituted -2H-chromenes and -4H-chromen-4-ones. Bioorg Med Chem 2014; 22(3): 1201-7.
[http://dx.doi.org/10.1016/j.bmc.2013.11.054] [PMID: 24360829]
[http://dx.doi.org/10.1016/j.bmc.2013.11.054] [PMID: 24360829]
[14]
Kamdar NR, Haveliwala DD, Mistry PT, Patel SK. Synthesis and evaluation of in vitro antitubercular activity and antimicrobial activity of some novel 4H-chromeno[2,3-d]pyrimidine via 2-amino-4-phenyl-4H-chromene-3-carbonitriles. Med Chem Res 2011; 20(7): 854-64.
[http://dx.doi.org/10.1007/s00044-010-9399-x]
[http://dx.doi.org/10.1007/s00044-010-9399-x]
[15]
Nitin K, Sushil K, Himanshu G, Sharma PK. 3-Hydroxy-2- (substituted phenyl) -4H-chromen-4-one derivatives- synthesis, spectral characterization and pharmacological screening. World Res J Biochem 2012; 1: 1.
[16]
Chauhan D, Hashim SR, Rani P, Kumar S, Shrimal N, Shastri D. Discovery of novel substituted N-(6-chloro-3-cyano-4-phenyl-4H-chromen-2-yl)-2-(4-chloro-phenoxy)-acetamide for biphasic anticancer and anticonvulsant activities. Med Chem 2019; 15: 1.
[17]
Chauhan D, Hashim SR, Rani P, et al. Discovery of Substituted N-(6-Chloro-3-cyano-4-phenyl-4H-chromen-2-yl)- 2-(4-chloro-phenoxy)-acetamide for Biphasic Anticancer and Anticonvulsant Activities. Med Chem 2021; 17(3): 203-15.
[http://dx.doi.org/10.2174/1573406415666191206101617] [PMID: 31808391]
[http://dx.doi.org/10.2174/1573406415666191206101617] [PMID: 31808391]
[18]
Tice RR, Agurell E, Anderson D, et al. Single cell gel/comet assay: Guidelines for in vitro and in vivo genetic toxicology testing. Environ Mol Mutagen 2000; 35(3): 206-21.
[http://dx.doi.org/10.1002/(SICI)1098-2280(2000)35:3<206:AID-EM8>3.0.CO;2-J] [PMID: 10737956]
[http://dx.doi.org/10.1002/(SICI)1098-2280(2000)35:3<206:AID-EM8>3.0.CO;2-J] [PMID: 10737956]
[19]
Lodhi L, Maity S, Kumar P, Saraf SA, Kaithwas G, Saha S. Evaluation of mechanism of hepatotoxicity of leflunomide using albino wistar rats. Afr J Pharm Pharmacol 2013; 7(24): 1625-31.
[http://dx.doi.org/10.5897/AJPP2013.3517]
[http://dx.doi.org/10.5897/AJPP2013.3517]
[20]
Sahdev AK, Raj V, Singh AK, et al. Ameliorative effects of pyrazinoic acid against oxidative and metabolic stress manifested in rats with dimethylhydrazine induced colonic carcinoma. Cancer Biol Ther 2017; 18(5): 304-13.
[http://dx.doi.org/10.1080/15384047.2017.1310341] [PMID: 28358223]
[http://dx.doi.org/10.1080/15384047.2017.1310341] [PMID: 28358223]
[21]
Rai A, Kumar U, Raj V, et al. Novel 1,4-benzothazines obliterate COX-2 mediated JAK-2/STAT-3 signals with potential regulation of oxidative and metabolic stress during colorectal cancer. Pharmacol Res 2018; 132: 188-203.
[http://dx.doi.org/10.1016/j.phrs.2017.12.010] [PMID: 29229353]
[http://dx.doi.org/10.1016/j.phrs.2017.12.010] [PMID: 29229353]
[22]
Greenwald RA. Handbook of methods for oxygen radical researchFree Radical Biology and Medicine. CRC Press 1987; p. 161.
[23]
Kim WR, Flamm SL, Di Bisceglie AM, Bodenheimer HC. Serum activity of alanine aminotransferase (ALT) as an indicator of health and disease. Hepatology 2008; 47(4): 1363-70.
[http://dx.doi.org/10.1002/hep.22109] [PMID: 18366115]
[http://dx.doi.org/10.1002/hep.22109] [PMID: 18366115]
[24]
Kushwaha PS, Raj V, Singh AK, et al. Antidiabetic effects of isolated sterols from Ficus racemosa leaves. RSC Advances 2015; 5(44): 35230-7.
[http://dx.doi.org/10.1039/C5RA00790A]
[http://dx.doi.org/10.1039/C5RA00790A]
[25]
Singh AK, Raj V, Keshari AK, et al. Isolated mangiferin and naringenin exert antidiabetic effect via PPAR γ/GLUT4 dual agonistic action with strong metabolic regulation. Chem Biol Interact 2018; 280: 33-44.
[http://dx.doi.org/10.1016/j.cbi.2017.12.007] [PMID: 29223569]
[http://dx.doi.org/10.1016/j.cbi.2017.12.007] [PMID: 29223569]
