BACKGROUND: Heterocyclic materials-containing thiazoles exhibited incredible importance in pharmaceutical chemistry and drug design due to their extensive biological properties.
METHODS: Synthesis of thiazoles and bis-thiazoles from the reaction of 2-((6-Nitrobenzo[ d][1,3]dioxol-5-yl)methylene)hydrazine-1-carbothioamide with hydrazonoyl chlorides in dioxane and in the existence of triethylamine as basic catalyst. The antioxidant, antiproliferative, and cytotoxicity efficacy of thiazoles and bis-thiazoles were measured.
RESULTS: In this work, novel series of 5-methyl-2-(2-(-(6-nitrobenzo[d][1,3]dioxol-5-yl)methylene) hydrazinyl)-4-(aryldiazenyl)thiazoles (4a-f) were prepared the reaction of hydrazonoyl chlorides 2a-f with 2-((6-nitrobenzo[d][1,3]dioxol-5-yl)methylene)hydrazine-1-carbothioamide (1) in dioxane and employing triethylamine as basic catalyst. Following the same procedure, bisthiazoles (6, 8, and 10) have been synthesized by utilizing bis-hydrazonoyl chlorides (5, 7, and 9) and carbothioamide 1 in a molar ratio (1:2), respectively. The distinctive features in the structure of isolated products were elucidated by spectroscopic tools and elemental analyses. The antioxidant, in vitro anti-proliferative, cytotoxicity, and anti-cancer efficacy of thiazoles and bis-thiazoles were evaluated. Compounds 4d and 4f were the most potent antioxidant agents. Gene expression of apoptosis markers and fragmentation assay of DNA were assessed to explore the biochemical mechanism of synthesized products. Thiazoles significantly inhibited cell growth and proliferation more than bis-thiazoles. They induced apoptosis through induction of apoptotic gene expression P53 and downregulation of antiapoptotic gene expression Bcl-2. Moreover, they induced fragmentation of DNA in cancer cells, indicating that they could be employed as anticancer agents by inhibiting tumor growth and progression and can be considered effective compounds in the strategy of anti-cancer agents' discovery.
CONCLUSION: Synthesis, DPPH Radical Scavenging, Cytotoxic activity, and Apoptosis Induction Efficacy based on Novel Thiazoles and Bis-thiazoles.
Rather R.A.; Bhagat M.; Cancer chemoprevention and piperine: Molecular mechanisms and therapeutic opportunities. Front Cell Dev Biol 2018,6,10
[DOI:
10.3389/fcell.2018.00010]
Siegel R.L.; Miller K.D.; Fuchs H.E.; Jemal A.; Cancer statistics, 2022. CA Cancer J Clin 2022,72(1),7-33
[DOI:
10.3322/caac.21708]
Chen Y.H.; Yang S.F.; Yang C.K.; Tsai H.D.; Chen T.H.; Chou M.C.; Hsiao Y.H.; Metformin induces apoptosis and inhibits migration by activating the AMPK/p53 axis and suppressing PI3K/AKT signaling in human cervical cancer cells. Mol Med Rep 2020,23(1),88
[DOI:
10.3892/mmr.2020.11725]
Kathawala R.J.; Gupta P.; Ashby C.R.; Chen Z.S.; The modulation of ABC transporter-mediated multidrug resistance in cancer: A review of the past decade. Drug Resist Updat 2015,18,1-17
[DOI:
10.1016/j.drup.2014.11.002]
Pawar S.; Kumar K.; Gupta M.K.; Rawal R.K.; Synthetic and medicinal perspective of fused-thiazoles as anticancer agents. Anticancer Agents Med Chem 2020,21(11),1379-1402
[DOI:
10.2174/1871520620666200728133017]
de Santana T.I.; Barbosa M.O.; Gomes P.A.T.M.; da Cruz A.C.N.; da Silva T.G.; Leite A.C.L.; Synthesis, anticancer activity and mechanism of action of new thiazole derivatives. Eur J Med Chem 2018,144,874-886
[DOI:
10.1016/j.ejmech.2017.12.040]
Jain S.; Pattnaik S.; Pathak K.; Kumar S.; Pathak D.; Jain S.; Vaidya A.; Anticancer potential of thiazole derivatives: A retrospective review. Mini Rev Med Chem 2018,18(8),640-655
[DOI:
10.2174/1389557517666171123211321]
Gadekar P.K.; Urunkar G.; Roychowdhury A.; Sharma R.; Bose J.; Khanna S.; Damre A.; Sarveswari S.; Design, synthesis and biological evaluation of 2,3-dihydroimidazo[2,1-b]thiazoles as dual EGFR and IGF1R inhibitors. Bioorg Chem 2021,115,105151
[DOI:
10.1016/j.bioorg.2021.105151]
Ayati A.; Emami S.; Asadipour A.; Shafiee A.; Foroumadi A.; Recent applications of 1,3-thiazole core structure in the identification of new lead compounds and drug discovery. Eur J Med Chem 2015,97,699-718
[DOI:
10.1016/j.ejmech.2015.04.015]
de Oliveira V.V.G.; Aranda de Souza M.A.; Cavalcanti R.R.M.; de Oliveira Cardoso M.V.; Leite A.C.L.; da Silva Junior V.A.; de Figueiredo R.C.B.Q.; Study of in vitro biological activity of thiazoles on Leishmania (Leishmania) infantum. J Glob Antimicrob Resist 2020,22,414-421
[DOI:
10.1016/j.jgar.2020.02.028]
Sharma P.C.; Bansal K.K.; Sharma A.; Sharma D.; Deep A.; Thiazole-containing compounds as therapeutic targets for cancer therapy. Eur J Med Chem 2020,188,112016
[DOI:
10.1016/j.ejmech.2019.112016]
Majidi Z.; Hosseinkhani S.; Amiri-Dashatan N.; Emamgholipour S.; Tutunchi S.; Hashemi J.; Ghorbani F.; Koushki M.; Effect of rosiglitazone on circulating malondialdehyde (MDA) level in diabetes based on a systematic review and meta-analysis of eight clinical trials. J Investig Med 2021,69(3),697-703
[DOI:
10.1136/jim-2020-001588]
Mahmoud H.K.; Sayed A.R.; Abdel-Aziz M.M.; Gomha S.M.; Synthesis of new thiazole clubbed imidazo[2,1-b]thiazole hybrid as antimycobacterial agents. Med Chem 2022,10(9),1100-1108
[DOI:
10.2174/1573406418666220413095854]
Sayed A.R.; Gomha S.M.; Abdelrazek F.M.; Farghaly M.S.; Hassan S.A.; Metz P.; Design, efficient synthesis and molecular docking of some novel thiazolyl-pyrazole derivatives as anticancer agents. BMC Chem 2019,13(1),116
[DOI:
10.1186/s13065-019-0632-5]
Al-Omair M.A.; Sayed A.R.; Youssef M.M.; Synthesis and biological evaluation of bisthiazoles and polythiazoles. Molecules 2018,23,23051133
[DOI:
10.3390/molecules23051133]
Aly A.A.; Brase S.; Hassan A.A.; Mohamed N.K.; El-Haleem L.E.A.; Nieger M.; Morsy N.M.; Alshammari M.B.; Ibrahim M.A.A.; Abdelhafez E.M.N.; Design, synthesis, and molecular docking of paracyclophanyl-thiazole hybrids as novel CDK1 inhibitors and apoptosis inducing anti-melanoma agents. Molecules 2020,25,25235569
[DOI:
10.3390/molecules25235569]
Dawoud N.T.A.; El-Fakharany E.M.; Abdallah A.E.; El-Gendi H.; Lotfy D.R.; Synthesis, and docking studies of novel heterocycles incorporating the indazolylthiazole moiety as antimicrobial and anticancer agents. Sci Rep 2022,12(1),3424
[DOI:
10.1038/s41598-022-07456-1]
Rashdan H.R.M.; Abdelmonsef A.H.; Shehadi I.A.; Gomha S.M.; Soliman A.M.M.; Mahmoud H.K.; Synthesis, molecular docking screening and anti-proliferative potency evaluation of some new imidazo[2,1-b]thiazole linked thiadiazole conjugates. Molecules 2020,25,25214997
[DOI:
10.3390/molecules25214997]
Mahmoud H.K.; Kassab R.M.; Gomha S.M.; Synthesis and characterization of some novel bis‐thiazoles. J Heterocycl Chem 2019,56(11),3157-3163
[DOI:
10.1002/jhet.3717]
Salem M.E.; Hosny M.; Darweesh A.F.; Elwahy A.H.M.; Synthesis of novel bis- and poly(aryldiazenylthiazoles). Synth Commun 2019,49(18),2319-2329
[DOI:
10.1080/00397911.2019.1620283]
Althagafi I.I.; Abouzied A.S.; Farghaly T.A.; Al-Qurashi N.T.; Alfaifi M.Y.; Shaaban M.R.; Abdel Aziz M.R.; Novel nano-sized bis -indoline derivatives as antitumor agents. J Heterocycl Chem 2019,56(2),391-399
[DOI:
10.1002/jhet.3410]
Farghaly T.A.; Abo Alnaja A.M.; El-Ghamry H.A.; Shaaban M.R.; Synthesis and DNA binding of novel bioactive thiazole derivatives pendent to N-phenylmorpholine moiety. Bioorg Chem 2020,102,104103
[DOI:
10.1016/j.bioorg.2020.104103]
Meriane D.; Genta-Jouve G.; Kaabeche M.; Michel S.; Boutefnouchet S.; Rapid identification of antioxidant compounds of Genista saharae Coss. and Dur. by combination of DPPH scavenging assay and HPTLC-MS. Molecules 2014,19(4),4369-4379
[DOI:
10.3390/molecules19044369]
Re R.; Pellegrini N.; Proteggente A.; Pannala A.; Yang M.; Rice-Evans C.; Antioxidant activity applying an improved ABTS radical cation decolorization assay. Free Radic Biol Med 1999,26(9-10),1231-1237
[DOI:
10.1016/S0891-5849(98)00315-3]
Mosmann T.; Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J Immunol Methods 1983,65,55-63
[DOI:
10.1016/0022-1759(83)90303-4]
Kim T.; Jung U.; Cho D.Y.; Chung A.S.; Se-Methylselenocysteine induces apoptosis through caspase activation in HL-60 cells. Carcinogenesis 2001,22(4),559-565
[DOI:
10.1093/carcin/22.4.559]
Zuo Y.; Shields S.K.; Chakraborty C.; Enhanced intrinsic migration of aggressive breast cancer cells by inhibition of Rac1 GTPase. Biochem Biophys Res Commun 2006,351,361-367
[DOI:
10.1016/j.bbrc.2006.10.043]
Li H.; Sanguinarine inhibits osteoclast formation and bone resorption via suppressing RANKL-induced activation of NF-؛خB and ERK signaling pathways. Biochem Biophys Res Commun 2013,430,951-956
[DOI:
10.1016/j.bbrc.2012.12.051]
Porichi O.; Nikolaidou M.E.; Apostolaki A.; Tserkezoglou A.; Arnogiannaki N.; Kassanos D.; Margaritis L.; Panotopoulou E.; BCL-2, BAX and P53 expression profiles in endometrial carcinoma as studied by real-time PCR and immunohistochemistry. Anticancer Res 2009,29(10),3977-3982
[DOI:
29/10/3977]
Sayed A.R.; Al-Faiyz Y.S.; Elsawy H.; Shaaban S.; Mohamed M.A.; Synthesis and biochemical studies of novel mon-azothiazoles and bis-azothiazoles based on 2-(4-(Dimethylamino)Benzylidene)hydrazine-1-carbothioamide. Polycycl Aromat Compd 2022,12,2049326
[DOI:
10.1080/10406638.2022.2049326]
dos Santos T.; Varela J.; Lynch I.; Salvati A.; Dawson K.A.; Effects of transport inhibitors on the cellular uptake of carboxylated polystyrene nanoparticles in different cell lines. PLoS One 2011,6(9),e24438
[DOI:
10.1371/journal.pone.0024438]
Andricopulo A.D.; Akoachere M.B.; Krogh R.; Nickel C.; McLeish M.J.; Kenyon G.L.; Arscott L.D.; Williams C.H.; Davioud-Charvet E.; Becker K.; Specific inhibitors of Plasmodium falciparum thioredoxin reductase as potential antimalarial agents. Bioorg Med Chem Lett 2006,16(8),2283-2292
[DOI:
10.1016/j.bmcl.2006.01.027]
Bangade V.M.; Mali P.R.; Meshram H.M.; Synthesis of potent anticancer substituted 5-benzimidazol-2-amino thiazoles controlled by bifunctional hydrogen bonding under microwave irradiations. J Org Chem 2021,86(9),6056-6065
[DOI:
10.1021/acs.joc.0c02542]
Sridhar R.; Perumal P.T.; Etti S.; Shanmugam G.; Ponnuswamy M.N.; Prabavathy V.R.; Mathivanan N.; Design, synthesis and anti-microbial activity of 1H-pyrazole carboxylates. Bioorg Med Chem Lett 2004,14(24),6035-6040
[DOI:
10.1016/j.bmcl.2004.09.066]
Dawood K.M.; Eldebss T.M.; El-Zahabi H.S.; Yousef M.H.; Metz P.; Synthesis of some new pyrazole-based 1,3-thiazoles and 1,3,4-thiadiazoles as anticancer agents. Eur J Med Chem 2013,70,740-779
[DOI:
10.1016/j.ejmech.2013.10.042]
Grigalius I.; Petrikaite V.; Relationship between antioxidant and anticancer activity of trihydroxyflavones. Molecules 2017,22(12),2169
[DOI:
10.3390/molecules22122169]
Volarevic V.; Djokovic B.; Jankovic M.G.; Harrell C.R.; Fellabaum C.; Djonov V.; Arsenijevic N.; Molecular mechanisms of cisplatin-induced nephrotoxicity: A balance on the knife edge between renoprotection and tumor toxicity. J Biomed Sci 2019,26(1),25
[DOI:
10.1186/s12929-019-0518-9]
Arora S.; Tandon S.; DNA fragmentation and cell cycle arrest: A hallmark of apoptosis induced by Ruta graveolens in human colon cancer cells. Homeopathy 2015,104,36-47
[DOI:
10.1016/j.homp.2014.10.001]
Li Q.X.; Yu D.H.; Liu G.; Ke N.; McKelvy J.; Wong-Staal F.; Selective anticancer strategies via intervention of the death pathways relevant to cell transformation. Cell Death Differ 2008,15,1197-1210
[DOI:
10.1038/cdd.2008.48]
Hientz K.; Mohr A.; Bhakta-Guha D.; Efferth T.; The role of p53 in cancer drug resistance and targeted chemotherapy. Oncotarget 2017,8(5),8921-8946
[DOI:
10.18632/oncotarget.13475]
Hardwick J.M.; Soane L.; Multiple functions of BCL-2 family proteins. Cold Spring Harb Perspect Biol 2013,5(2),a008722
[DOI:
10.1101/cshperspect.a008722]
Reed J.C.; Bcl-2-family proteins and hematologic malignancies: History and future prospects. Blood 2008,111(7),3322-3330
[DOI:
10.1182/blood-2007-09-078162]
