Design, Synthesis, and Biological Assessment of Bis-thiazole Derivatives as Promising Anticancer Agents with Molecular Docking Insights

Tariq   Z.   Abolibda; Magdi   E.A.   Zaki; Waleed   E.   Boraie; Basant      Farag; Sobhi   M.   Gomha
doi:10.2174/0115701794379474250528170604
Abstract

Introduction: Thiazoles and bis-thiazoles are recognized for their anticancer and antitubercular properties, making them crucial in medicinal chemistry. This study focuses on synthesizing and evaluating novel bis-thiazole derivatives.
Materials and Methods: Bis-thiosemicarbazone derivative 3 was used as a precursor to synthesize bis-thiazole (6a-f, 12a-h) and bis-thiazolone (9a-d) derivatives through reactions with appropriate reagents. Anticancer activity was screened using the MTT assay on HCT-116 cells, while antitubercular activity was tested using the microplate Alamar blue assay (MABA). The derivatives were synthesized under optimized reflux conditions and characterized using spectroscopic techniques. Biological assays evaluated their therapeutic potential.
Results: The compounds displayed variable cytotoxicity and antitubercular efficacy. Molecular docking studies on dihydrofolate reductase (DHFR) revealed significant interactions, suggesting potential mechanisms of action.
Discussion: The results highlight the influence of structural features on biological activity, with active compounds showing favorable interactions and docking scores.
Conclusion: Bis-thiazole and bis-thiazolone derivatives exhibit promising anticancer and antitubercular potential, warranting further investigation for therapeutic applications.
Keywords: Bis-heterocycles, hydrazonoyl halides, heterocyclization, anticancer, molecular docking, and ADMET studies.
« Previous Next »
Graphical Abstract

[1]
Menta, E.; Palumbo, M. Novel antineoplastic agents. Expert Opin. Ther. Pat.,  1997, 7(12), 1401-1426.
 [http://dx.doi.org/10.1517/13543776.7.12.1401]

[2]
Nussbaumer, S.; Bonnabry, P.; Veuthey, J.L.; Fleury-Souverain, S. Analysis of anticancer drugs: A review. Talanta,  2011, 85(5), 2265-2289.
 [http://dx.doi.org/10.1016/j.talanta.2011.08.034] [PMID: 21962644]

[3]
Rebucci, M.; Michiels, C. Molecular aspects of cancer cell resistance to chemotherapy. Biochem. Pharmacol.,  2013, 85(9), 1219-1226.
 [http://dx.doi.org/10.1016/j.bcp.2013.02.017] [PMID: 23435357]

[4]
Holohan, C.; Van Schaeybroeck, S.; Longley, D.B.; Johnston, P.G. Cancer drug resistance: An evolving paradigm. Nat. Rev. Cancer,  2013, 13(10), 714-726.
 [http://dx.doi.org/10.1038/nrc3599] [PMID: 24060863]

[5]
Rosa, R.; Monteleone, F.; Zambrano, N.; Bianco, R. In vitro and in vivo models for analysis of resistance to anticancer molecular therapies. Curr. Med. Chem.,  2014, 21(14), 1595-1606.
 [http://dx.doi.org/10.2174/09298673113209990226] [PMID: 23992330]

[6]
da Silva, E.B.; Oliveira e Silva, D.A.; Oliveira, A.R.; da Silva Mendes, C.H.; dos Santos, T.A.R.; da Silva, A.C.; de Castro, M.C.A.; Ferreira, R.S.; Moreira, D.R.M.; Cardoso, M.V.O.; de Simone, C.A.; Pereira, V.R.A.; Leite, A.C.L.; Leite, A.C. Desing and synthesis of potent anti-Trypanosoma cruzi agents new thiazoles derivatives which induce apoptotic parasite death. Eur. J. Med. Chem.,  2017, 130, 39-50.
 [http://dx.doi.org/10.1016/j.ejmech.2017.02.026] [PMID: 28242550]

[7]
Espيndola, J.W.P.; Cardoso, M.V.O.; Filho, G.B.O.; Oliveira e Silva, D.A.; Moreira, D.R.M.; Bastos, T.M.; Simone, C.A.; Soares, M.B.P.; Villela, F.S.; Ferreira, R.S.; Castro, M.C.A.B.; Pereira, V.R.A.; Murta, S.M.F.; Sales Junior, P.A.; Romanha, A.J.; Leite, A.C.L. Synthesis and structure–activity relationship study of a new series of antiparasitic aryloxyl thiosemicarbazones inhibiting Trypanosoma cruzi cruzain. Eur. J. Med. Chem.,  2015, 101, 818-835.
 [http://dx.doi.org/10.1016/j.ejmech.2015.06.048] [PMID: 26231082]

[8]
Magalhaes Moreira, D.R.; de Oliveira, A.D.T.; Teixeira de Moraes Gomes, P.A.; de Simone, C.A.; Villela, F.S.; Ferreira, R.S.; da Silva, A.C.; dos Santos, T.A.R.; Brelaz de Castro, M.C.A.; Pereira, V.R.A.; Leite, A.C.L. Conformational restriction of aryl thiosemicarbazones produces potent and selective anti-Trypanosoma cruzi compounds which induce apoptotic parasite death. Eur. J. Med. Chem.,  2014, 75, 467-478.
 [http://dx.doi.org/10.1016/j.ejmech.2014.02.001] [PMID: 24561675]

[9]
de Melos, J.L.R.; Torres-Santos, E.C.; Faiões, V.S.; de Nigris Del Cistia, C.; Sant’Anna, C.M.R.; Rodrigues-Santos, C.E.; Echevarria, A. 
          	 Novel 3,4-methylenedioxyde-6-X-benzaldehyde-thiosemicarbazones: Synthesis and antileishmanial effects against Leishmania amazonensis. Eur. J. Med. Chem.,  2015, 103, 409-417.
 [http://dx.doi.org/10.1016/j.ejmech.2015.09.009] [PMID: 26375353]

[10]
da Silva, J.B.P.; Navarro, D.M.A.F.; da Silva, A.G.; Santos, G.K.N.; Dutra, K.A.; Moreira, D.R.; Ramos, M.N.; Espíndola, J.W.P.; de Oliveira, A.D.T.; Brondani, D.J.; Leite, A.C.L.; Hernandes, M.Z.; Pereira, V.R.A.; da Rocha, L.F.; de Castro, M.C.A.B.; de Oliveira, B.C.; Lan, Q.; Merz, K.M. 
          	 Thiosemicarbazones as Aedes aegypti larvicidal. Eur. J. Med. Chem.,  2015, 100, 162-175.
 [http://dx.doi.org/10.1016/j.ejmech.2015.04.061] [PMID: 26087027]

[11]
Netalkar, P.P.; Netalkar, S.P.; Revankar, V.K. Transition metal complexes of thiosemicarbazone: Synthesis, structures and in vitro antimicrobial studies. Polyhedron,  2015, 100, 215-222.
 [http://dx.doi.org/10.1016/j.poly.2015.07.075]

[12]
Zhang, X.M.; Guo, H.; Li, Z.S.; Song, F.H.; Wang, W.M.; Dai, H.Q.; Zhang, L.X.; Wang, J.G. Synthesis and evaluation of isatin-β-thiosemicarbazones as novel agents against antibiotic-resistant Gram-positive bacterial species. Eur. J. Med. Chem.,  2015, 101, 419-430.
 [http://dx.doi.org/10.1016/j.ejmech.2015.06.047] [PMID: 26185006]

[13]
Zaltariov, M.F.; Hammerstad, M.; Arabshahi, H.J.; Jovanović, K.; Richter, K.W.; Cazacu, M.; Shova, S.; Balan, M.; Andersen, N.H.; Radulović, S.; Reynisson, J.; Andersson, K.K.; Arion, V.B. New iminodiacetate-thiosemicarbazone hybrids and their copper (II) complexes as potential ribonucleotide reductase R2 inhibitors with high antiproliferative activity. Inorg. Chem.,  2017, 56(6), 3532-3549.
 [http://dx.doi.org/10.1021/acs.inorgchem.6b03178] [PMID: 28252952]

[14]
Rogolino, D.; Cavazzoni, A.; Gatti, A.; Tegoni, M.; Pelosi, G.; Verdolino, V.; Fumarola, C.; Cretella, D.; Petronini, P.G.; Carcelli, M. Anti-proliferative effects of copper(II) complexes with hydroxyquinoline-thiosemicarbazone ligands. Eur. J. Med. Chem.,  2017, 128, 140-153.
 [http://dx.doi.org/10.1016/j.ejmech.2017.01.031] [PMID: 28182987]

[15]
Hu, W.; Zhou, W.; Xia, C.; Wen, X. Synthesis and anticancer activity of thiosemicarbazones. Bioorg. Med. Chem. Lett.,  2006, 16(8), 2213-2218.
 [http://dx.doi.org/10.1016/j.bmcl.2006.01.048] [PMID: 16458509]

[16]
Liu, M.; Xiao, L.; Dong, Y.; Liu, Y.; Cai, L.; Xiong, W.; Yao, Y.; Yin, M.; Liu, Q. Characterization of the anticancer effects of S115, a novel heteroaromatic thiosemicarbazone compound, in vitro and in vivo. Acta Pharmacol. Sin.,  2014, 35(10), 1302-1310.
 [http://dx.doi.org/10.1038/aps.2014.71] [PMID: 25220642]

[17]
Cardoso, M.V.O.; Siqueira, L.R.P.; Silva, E.B.; Costa, L.B.; Hernandes, M.Z.; Rabello, M.M.; Ferreira, R.S.; da Cruz, L.F.; Magalhães Moreira, D.R.; Pereira, V.R.A.; de Castro, M.C.A.B.; Bernhardt, P.V.; Leite, A.C.L. 
          	 2-Pyridyl thiazoles as novel anti-Trypanosoma cruzi agents: Structural design, synthesis and pharmacological evaluation. Eur. J. Med. Chem.,  2014, 86, 48-59.
 [http://dx.doi.org/10.1016/j.ejmech.2014.08.012] [PMID: 25147146]

[18]
Abdellatif, K.R.A.; El-Wareth, G.A.A.; El-Badry, O.M.; Ragab, H.M.; El-Enany, M.M. Synthesis and antimicrobial evaluation of certain purine, benzothiazole, and thiazole systems substituted with dialkylaminoalkyl-o-cresols. J. Basic Appl. Sci.,  2015, 4, 52-59.

[19]
Grozav, A.; Găină, L.; Pileczki, V.; Crisan, O.; Silaghi-Dumitrescu, L.; Therrien, B.; Zaharia, V.; Berindan-Neagoe, I. The synthesis and antiproliferative activities of new arylidene-hydrazinyl-thiazole derivatives. Int. J. Mol. Sci.,  2014, 15(12), 22059-22072.
 [http://dx.doi.org/10.3390/ijms151222059] [PMID: 25470024]

[20]
dos Santos, T.A.R.; da Silva, A.C.; Silva, E.B.; Gomes, P.A.T.M.; Espíndola, J.W.P.; Cardoso, M.V.O.; Moreira, D.R.M.; Leite, A.C.L.; Pereira, V.R.A. Antitumor and immunomodulatory activities of thiosemicarbazones and 1,3-Thiazoles in Jurkat and HT-29 cells. Biomed. Pharmacother.,  2016, 82, 555-560.
 [http://dx.doi.org/10.1016/j.biopha.2016.05.038] [PMID: 27470396]

[21]
Aliabadi, A.; Shamsa, F.; Ostad, S.N.; Emami, S.; Shafiee, A.; Davoodi, J.; Foroumadi, A. Synthesis and biological evaluation of 2-phenylthiazole-4-carboxamide derivatives as anticancer agents. Eur. J. Med. Chem.,  2010, 45(11), 5384-5389.
 [http://dx.doi.org/10.1016/j.ejmech.2010.08.063] [PMID: 20846760]

[22]
Banimustafa, M.; Kheirollahi, A.; Safavi, M.; Kabudanian Ardestani, S.; Aryapour, H.; Foroumadi, A.; Emami, S. Synthesis and biological evaluation of 3-(trimethoxyphenyl)-2(3H)-thiazole thiones as combretastatin analogs. Eur. J. Med. Chem.,  2013, 70, 692-702.
 [http://dx.doi.org/10.1016/j.ejmech.2013.10.046] [PMID: 24219991]

[23]
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.
 [http://dx.doi.org/10.1016/j.ejmech.2015.04.015] [PMID: 25934508]

[24]
Das, D.; Sikdar, P.; Bairagi, M. Recent developments of 2-aminothiazoles in medicinal chemistry. Eur. J. Med. Chem.,  2016, 109, 89-98.
 [http://dx.doi.org/10.1016/j.ejmech.2015.12.022] [PMID: 26771245]

[25]
Limban, C.; Chifiriuc, M.C.B.; Missir, A.V.; Chiriţă, I.C.; Bleotu, C. Antimicrobial activity of some new thioureides derived from 2-(4-chlorophenoxymethyl)benzoic acid. Molecules,  2008, 13(3), 567-580.
 [http://dx.doi.org/10.3390/molecules13030567] [PMID: 18463566]

[26]
Hussein, A.M.; Gomha, S.M.; El-Ghany, N.A.A.; Zaki, M.E.A.; Farag, B.; Al-Hussain, S.A.; Sayed, A.R.; Zaki, Y.H.; Mohamed, N.A. Green biocatalyst for ultrasound-assisted thiazole derivatives: Synthesis, antibacterial evaluation, and docking analysis. ACS Omega,  2024, 9(12), 13666-13679.
 [http://dx.doi.org/10.1021/acsomega.3c07785] [PMID: 38559991]

[27]
Limban, C.; Marutescu, L.; Chifiriuc, M.C. Synthesis, spectroscopic properties and antipathogenic activity of new thiourea derivatives. Molecules,  2011, 16(9), 7593-7607.
 [http://dx.doi.org/10.3390/molecules16097593] [PMID: 21900862]

[28]
John, M.; Beale, J.; Block, J.H. Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry, 12th ed; Wolters Kluwer Health, 2012. 

[29]
Al-Omair, M.A.; Sayed, A.R.; Youssef, M.M. Synthesis and biological evaluation of bisthiazoles and polythiazoles. Molecules,  2018, 23(5), 1133.
 [http://dx.doi.org/10.3390/molecules23051133] [PMID: 29747479]

[30]
Kouatly, O.; Geronikaki, A.; Kamoutsis, C.; Hadjipavlou-Litina, D.; Eleftheriou, P. Adamantane derivatives of thiazolyl-N-substituted amide, as possible non-steroidal anti-inflammatory agents. Eur. J. Med. Chem.,  2009, 44(3), 1198-1204.
 [http://dx.doi.org/10.1016/j.ejmech.2008.05.029] [PMID: 18603333]

[31]
Abolibda, T.Z.; El-Sayed, A.A.A.A.; Farag, B.; Zaki, M.E.A.; Alrehaily, A.; Elbadawy, H.M.; Al-Shahri, A.A.; Alsenani, S.R.; Gomha, S.M. Novel thiazolyl-pyrimidine derivatives as potential anticancer agents: Synthesis, biological evaluation, and molecular docking studies. Results Chem.,  2025, 13, 102008.
 [http://dx.doi.org/10.1016/j.rechem.2024.102008]

[32]
Jackson, R.C.; Hart, L.I.; Harrap, K.R. Intrinsic resistance to methotrexate of cultured mammalian cells in relation to the inhibition kinetics of their dihydrololate reductases. Cancer Res.,  1976, 36(6), 1991-1997.
 [PMID: 5189]

[33]
Goldie, J.H.; Krystal, G.; Hartley, D.; Gudauskas, G.; Dedhar, S. A methotrexate insensitive variant of folate reductase present in two lines of methotrexate-resistant L5178Y cells. Eur. J. Cancer,  1980, 16(12), 1539-1546.
 [http://dx.doi.org/10.1016/0014-2964(80)90026-2] [PMID: 7227429]

[34]
Kobayashi, H.; Takemura, Y.; Ohnuma, T. Variable expression of RFC1 in human leukemia cell lines resistant to antifolates. Cancer Lett.,  1998, 124(2), 135-142.
 [http://dx.doi.org/10.1016/S0304-3835(97)00464-3] [PMID: 9500202]

[35]
Assaraf, Y.G. Molecular basis of antifolate resistance. Cancer Metastasis Rev.,  2007, 26(1), 153-181.
 [http://dx.doi.org/10.1007/s10555-007-9049-z] [PMID: 17333344]

[36]
Abali, E.E.; Skacel, N.E.; Celikkaya, H.; Hsieh, Y.C. Regulation of human dihydrofolate reductase activity and expression. Vitam. Horm.,  2008, 79, 267-292.
 [http://dx.doi.org/10.1016/S0083-6729(08)00409-3] [PMID: 18804698]

[37]
Dolnick, B.J.; Berenson, R.J.; Bertino, J.R.; Kaufman, R.J.; Nunberg, J.H.; Schimke, R.T. Correlation of dihydrofolate reductase elevation with gene amplification in a homogeneously staining chromosomal region in L5178Y cells. J. Cell Biol.,  1979, 83(2), 394-402.
 [http://dx.doi.org/10.1083/jcb.83.2.394] [PMID: 500787]

[38]
Song, B.; Wang, Y.; Kudo, K.; Gavin, E.J.; Xi, Y.; Ju, J. miR-192 Regulates dihydrofolate reductase and cellular proliferation through the p53-microRNA circuit. Clin. Cancer Res.,  2008, 14(24), 8080-8086.
 [http://dx.doi.org/10.1158/1078-0432.CCR-08-1422] [PMID: 19088023]

[39]
Jang, G.R.; Harris, R.Z.; Lau, D.T. Pharmacokinetics and its role in small molecule drug discovery research. Med. Res. Rev.,  2001, 21(5), 382-396.
 [http://dx.doi.org/10.1002/med.1015] [PMID: 11579439]

[40]
Zaki, Y.H.; Gomha, S.M.; Farag, B.; Zaki, M.E.A.; Hussein, A.M. Synthesis, characterization, and in silico studies of substituted 2,3-dihydro-1,3,4-thiadiazole derivatives. Results Chem.,  2025, 13, 101977.
 [http://dx.doi.org/10.1016/j.rechem.2024.101977]

[41]
Thompson, T. Early ADME in support of drug discovery: The role of metabolic stability studies. Curr. Drug Metab.,  2000, 1(3), 215-241.
 [http://dx.doi.org/10.2174/1389200003339018] [PMID: 11465046]

[42]
Merlot, C. Computational toxicology: A tool for early safety evaluation. Drug Discov. Today,  2010, 15(1-2), 16-22.
 [http://dx.doi.org/10.1016/j.drudis.2009.09.010] [PMID: 19835978]

[43]
Eddershaw, P.J.; Beresford, A.P.; Bayliss, M.K. ADME/PK as part of a rational approach to drug discovery. Drug Discov. Today,  2000, 5(9), 409-414.
 [http://dx.doi.org/10.1016/S1359-6446(00)01540-3] [PMID: 10931658]

[44]
Gomha, S.M.; El-Sayed, A.A.A.A.; Zaki, M.E.A.; Alrehaily, A.; Elbadawy, H.M.; Al-Shahri, A.A.; Alsenani, S.R.; Abouzied, A.S. Synthesis, in vitro and in silico studies of novel Bis‐triazolopyridopyrimidines from curcumin analogues as potential aromatase agents. Chem. Biodivers.,  2024, 21(8), e202400701.
 [http://dx.doi.org/10.1002/cbdv.202400701] [PMID: 38829745]

[45]
Gomha, S.M.; Riyadh, S.M.; El-Sayed, A.A.A.A.; Abdallah, A.M.; Zaki, M.E.A.; Alrehaily, A.; Elbadawy, H.M.; Al-Shahri, A.A.; Alsenani, S.R.; Hussein, A.M. Grinding-assisted synthesis of novel arylhydrazono curcumin analogues and bis-pyrazolines as cyclin-dependent kinases (CDKs) inhibitors. Inorg. Chem. Commun.,  2024, 169, 113128.
 [http://dx.doi.org/10.1016/j.inoche.2024.113128]

[46]
Gomha, S.M.; El-Sayed, A.A.A.A.; Alrehaily, A.; Elbadawy, H.M.; Farag, B.; Al-Shahri, A.A.; Alsenani, S.R.; Abdelgawad, F.E.; Zaki, M.E.A. Synthesis, molecular docking, in silico study, and evaluation of bis-thiazole-based curcumin derivatives as potential antimicrobial agents. Results Chem.,  2024, 7, 101504.
 [http://dx.doi.org/10.1016/j.rechem.2024.101504]

[47]
Ouf, S.A.; Gomha, S.M.; Farag, B.; Zaki, M.E.A.; Ewies, M.M.; Sharawy, I.A.A.; Khalil, F.O.; Mahmoud, H.K. Synthesis of novel Bis-1,2,4-Triazolo[3,4-b][1,3,4]Thiadiazines from natural camphoric acid as potential anti-candidal agents. Results Chem.,  2024, 7, 101406.
 [http://dx.doi.org/10.1016/j.rechem.2024.101406]

[48]
Kassab, R.M.; Al-Hussain, S.A.; Abdelmonsef, A.H.; Zaki, M.E.; Gomha, S.M.; Muhammad, Z.A. Novel Bis-Thiazole derivatives as HSV-1 inhibitors through targeting surface glycoprotein D: An efficient synthesis, characterization, biological evaluation, and molecular docking study. Future Med. Chem.,  2024, 16, 27-41.
 [http://dx.doi.org/10.4155/fmc-2023-0210] [PMID: 38063202]

[49]
Mohamed, M.A.; Abouzied, A.S.; Reyad, A.; Sayed Abdelsalam Zaki, M.E.; Abdelgawad, F.E.; Al-Humaidi, J.Y.; Gomha, S.M. Novel terpyridines as Staphylococcus aureus gyrase inhibitors: Efficient synthesis and antibacterial assessment via solvent-drop grinding. Future Med. Chem.,  2024, 16(3), 205-220.
 [http://dx.doi.org/10.4155/fmc-2023-0278] [PMID: 38230640]

[50]
Kassab, R.M.; Gomha, S.M.; Muhammad, Z.A.; El-khouly, A.S. Synthesis, biological profile, and molecular docking of some new bis-fused imidazole templates and investigation of their cytotoxic potential as anti-tubercular and/or anticancer prototypes. Med. Chem.,  2021, 17(8), 875-886.
 [http://dx.doi.org/10.2174/1573406417666201208121458] [PMID: 33292124]

[51]
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.
 [http://dx.doi.org/10.1002/jhet.3717]

[52]
Abdelrazek, F.M.; Gomha, S.M.; Metz, P.; Abdalla, M.M. Synthesis of some novel 1,4-phenylene-bis-thiazolyl derivatives and their anti-hypertensive α-blocking activity screening. J. Heterocycl. Chem.,  2017, 54(1), 618-623.
 [http://dx.doi.org/10.1002/jhet.2633]

[53]
Gomha, S.; Kheder, N.; Abdelhamid, A.; Mabkhot, Y. One pot single step synthesis and biological evaluation of some novel bis (1,3,4-thiadiazole) derivatives as potential cytotoxic agents. Molecules,  2016, 21(11), 1532.
 [http://dx.doi.org/10.3390/molecules21111532] [PMID: 27854300]

[54]
Mosmann, T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J. Immunol. Methods,  1983, 65(1-2), 55-63.
 [http://dx.doi.org/10.1016/0022-1759(83)90303-4] [PMID: 6606682]

[55]
Gomha, S.M.; Riyadh, S.M.; Mahmmoud, E.A.; Elaasser, M.M. Synthesis and anticancer activity of arylazothiazoles and 1,3,4-thiadiazoles using chitosan-grafted-poly(4-vinylpyridine) as a novel copolymer basic catalyst. Chem. Heterocycl. Compd.,  2015, 51(11-12), 1030-1038.
 [http://dx.doi.org/10.1007/s10593-016-1815-9]

[56]
Raimondi, M.V.; Randazzo, O.; La Franca, M.; Barone, G.; Vignoni, E.; Rossi, D.; Collina, S. 2-DHFR inhibitors: Reading the past for discovering novel anticancer agents. Molecules,  2019, 24(6), 1140.
 [http://dx.doi.org/10.3390/molecules24061140] [PMID: 30909399]

[57]
Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev.,  2012, 64, 4-17.
 [http://dx.doi.org/10.1016/j.addr.2012.09.019] [PMID: 11259830]

[58]
Daina, A.; Michielin, O.; Zoete, V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep.,  2017, 7(1), 42717.
 [http://dx.doi.org/10.1038/srep42717] [PMID: 28256516]

[59]
Daina, A.; Michielin, O.; Zoete, V. iLOGP: a simple, robust, and efficient description of n-octanol/water partition coefficient for drug design using the GB/SA approach. J. Chem. Inf. Model.,  2014, 54(12), 3284-3301.
 [http://dx.doi.org/10.1021/ci500467k] [PMID: 25382374]

[60]
Kola, I.; Landis, J. Can the pharmaceutical industry reduce attrition rates? Nat. Rev. Drug Discov.,  2004, 3(8), 711-716.
 [http://dx.doi.org/10.1038/nrd1470] [PMID: 15286737]

[61]
Lipinski, C.A. Lead- and drug-like compounds: The rule-of-five revolution. Drug Discov. Today. Technol.,  2004, 1(4), 337-341.
 [http://dx.doi.org/10.1016/j.ddtec.2004.11.007] [PMID: 24981612]

[62]
Karami, T.K.; Hailu, S.; Feng, S.; Graham, R.; Gukasyan, H.J. Eyes on Lipinski’s rule of five: A New “rule of thumb” for physicochemical design space of ophthalmic drugs. J. Ocul. Pharmacol. Ther.,  2022, 38(1), 43-55.
 [http://dx.doi.org/10.1089/jop.2021.0069] [PMID: 34905402]

[63]
Pires, D.E.V.; Blundell, T.L.; Ascher, D.B. pkCSM: predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures. J. Med. Chem.,  2015, 58(9), 4066-4072.
 [http://dx.doi.org/10.1021/acs.jmedchem.5b00104] [PMID: 25860834]

[64]
Obach, R.S.; Lombardo, F.; Waters, N.J. Trend analysis of a database of intravenous pharmacokinetic parameters in humans for 670 drug compounds. Drug Metab. Dispos.,  2008, 36(7), 1385-1405.
 [http://dx.doi.org/10.1124/dmd.108.020479] [PMID: 18426954]

[65]
Ahmed, J.; Worth, C.L.; Thaben, P.; Matzig, C.; Blasse, C.; Dunkel, M.; Preissner, R. FragmentStore--a comprehensive database of fragments linking metabolites, toxic molecules and drugs. Nucleic Acids Res.,  2011, 39(Database), D1049-D1054.
 [http://dx.doi.org/10.1093/nar/gkq969] [PMID: 20965964]

[66]
Cumming, J.G.; Davis, A.M.; Muresan, S.; Haeberlein, M.; Chen, H. Chemical predictive modelling to improve compound quality. Nat. Rev. Drug Discov.,  2013, 12(12), 948-962.
 [http://dx.doi.org/10.1038/nrd4128] [PMID: 24287782]

[67]
Hosny, M.; Salem, M.E.; Darweesh, A.F.; Elwahy, A.H.M. Synthesis of novel bis(thiazolylchromen-2-one) derivatives linked to alkyl spacer via phenoxy group. J. Heterocycl. Chem.,  2018, 55(10), 2342-2348.
 [http://dx.doi.org/10.1002/jhet.3296]

[68]
Shawali, A.S.; Gomha, S.M. Regioselectivity in 1,5-electrocyclization of N-[as-triazin-3-yl]nitrilimines. Synthesis of s-triazolo[4,3-b]-as-triazin-7(8H)-ones. Tetrahedron,  2002, 58(42), 8559-8564.
 [http://dx.doi.org/10.1016/S0040-4020(02)00946-8]

[69]
Gomha, S.M.; Abdel-Aziz, H.A. Enaminones as building blocks in heterocyclic preparations: Synthesis of novel Pyrazoles, Pyrazolo[3,4-d]pyridazines, Pyrazolo[1,5-a]pyrimidines, and Pyrido[2,3-d]pyrimidines linked to Imidazo[2,1-b]thiazole system. Heterocycles,  2012, 85, 2291-2303.
 [http://dx.doi.org/10.3987/COM-12-12531]

[70]
Badrey, M.G.; Gomha, S.M. 3-Amino-8-Hydroxy-4-Imino-6-Methyl-5-Phenyl-4,5-Dihydro-3H-Chromeno[2,3-d]pyrimidine: An efficient precursor for novel synthesis of Triazines and Triazepines as potential anti-tumor agents. Molecules,  2012, 17, 11538-11553.
 [http://dx.doi.org/10.3390/molecules171011538] [PMID: 23018926]

[71]
Raimondi, M.V.; Randazzo, O.; La Franca, M.; Barone, G.; Vignoni, E.; Rossi, D.; Collina, S. DHFR inhibitors: Reading the past for discovering novel anticancer agents. Molecules,  2019, 24(6), 1140.
 [http://dx.doi.org/10.3390/molecules24061140] [PMID: 30909399]

[72]
Dulucq, S.; St-Onge, G.; Gagné, V.; Ansari, M.; Sinnett, D.; Labuda, D.; Moghrabi, A.; Krajinovic, M. DNA variants in the dihydrofolate reductase gene and outcome in childhood ALL. Blood,  2008, 111(7), 3692-3700.
 [http://dx.doi.org/10.1182/blood-2007-09-110593] [PMID: 18096764]

[73]
Saha, S.; Jungas, T.; Ohayon, D.; Audouard, C.; Ye, T.; Fawal, M.A.; Davy, A. Dihydrofolate reductase activity controls neurogenic transitions in the developing neocortex. Development,  2023, 150(20), dev201696.
 [http://dx.doi.org/10.1242/dev.201696] [PMID: 37665322]

[74]
Dunbar, J.; Yennawar, H.P.; Banerjee, S.; Luo, J.; Farber, G.K. The effect of denaturants on protein structure. Protein Sci.,  1997, 6(8), 1727-1733.
 [http://dx.doi.org/10.1002/pro.5560060813] [PMID: 9260285]

[75]
Chawla, P.; Teli, G.; Gill, R.K.; Narang, R.K. An insight into synthetic strategies and recent developments of dihydrofolate reductase inhibitors. ChemistrySelect,  2021, 6(43), 12101-12145.
 [http://dx.doi.org/10.1002/slct.202102555]

[76]
Sawant, S.D.; Sahu, M.; Nerkar, A.G. Quinazolinone platinum metal complexes: In silico design, synthesis and evaluation of anticancer activity. Asian J. Chem.,  2018, 30(10), 2164-2170.
 [http://dx.doi.org/10.14233/ajchem.2018.21330]

[77]
Muhammad, Z.; Edrees, M.; Faty, R.; Gomha, S.; Alterary, S.; Mabkhot, Y. Synthesis, antitumor evaluation and molecular docking of new morpholine-based heterocycles. Molecules,  2017, 22(7), 1211.
 [http://dx.doi.org/10.3390/molecules22071211] [PMID: 28726760]

[78]
Tang, Y-Q.; Lim, J.Y.; Gew, L.T. Biocomputational-mediated screening and molecular docking platforms for discovery of coumarin-derived antimelanogenesis agents. Zhonghua Pifuke Yixue Zazhi,  2023, 41(1), 8-17.
 [http://dx.doi.org/10.4103/ds.DS-D-22-00087]
Rights & Permissions Print Cite
Article Metrics
24
2
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/0115701794379474250528170604	Print ISSN 1570-1794
Publisher Name Bentham Science Publisher	Online ISSN 1875-6271
Current Organic Synthesis

Design, Synthesis, and Biological Assessment of Bis-thiazole Derivatives as Promising Anticancer Agents with Molecular Docking Insights

Abstract

Graphical Abstract

Related Journals

Related Books
