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Combinatorial Chemistry & High Throughput Screening

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ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

Research Article

Synthesis, Antitumor Activity and Molecular Docking Studies on Seven Novel Thiazacridine Derivatives

Author(s): Marcel L. Almeida, Douglas C.F. Viana , Valécia C.M. da Costa, Flaviana A. dos Santos, Michelly C. Pereira, Maira G.R. Pitta , Moacyr J.B. de Melo Rêgo, Ivan R. Pitta and Marina G.R. Pitta*

Volume 23, Issue 5, 2020

Page: [359 - 368] Pages: 10

DOI: 10.2174/1386207323666200319105239

Price: $65

Abstract

Aim and Objective: In the last decades, cancer has become a major problem in public health all around the globe. Chimeric chemical structures have been established as an important trend on medicinal chemistry in the last years. Thiazacridines are hybrid molecules composed of a thiazolidine and acridine nucleus, both pharmacophores that act on important biological targets for cancer. By the fact it is a serious disease, seven new 3-acridin-9-ylmethyl-thiazolidine-2,4-dione derivatives were synthesized, characterized, analyzed by computer simulation and tested in tumor cells. In order to find out if the compounds have therapeutic potential.

Materials and Methods: Seven new 3-acridin-9-ylmethyl-thiazolidine-2,4-dione derivatives were synthesized through Michael addition and Knoevenagel condensation strategies. Characterization was performed by NMR and Infrared spectroscopy techniques. Regarding biological activity, thiazacridines were tested against solid and hematopoietic tumoral cell lines, namely Jurkat (acute T-cell leukemia); HL-60 (acute promyelocytic leukemia); DU 145 (prostate cancer); MOLT-4 (acute lymphoblastic leukemia); RAJI (Burkitt's lymphoma); K562 (chronic myelogenous leukemia) and normal cells PBMC (healthy volunteers). Molecular docking analysis was also performed in order to assess major targets of these new compounds. Cell cycle and clonogenic assay were also performed.

Results: Compound LPSF/AA-62 (9f) exhibited the most potent anticancer activity against HL-60 (IC50 3,7±1,7 μM), MOLT-4 (IC50 5,7±1,1 μM), Jurkat (IC50 18,6 μM), Du-145 (IC50 20±5 μM) and Raji (IC50 52,3±9,2 μM). While the compound LPSF/AA-57 (9b) exhibited anticancer activity against the K562 cell line (IC50 51,8±7,8 μM). Derivative LPSF/AA-62 (9f) did not interfere in the cell cycle phases of the Molt-4 lineage. However, the LPSF/AA-62 (9f) derivative significantly reduced the formation of prostate cancer cell clones. The compound LPSF/AA-62 (9f) has shown strong anchorage stability with enzymes topoisomerases 1 and 2, in particular due the presence of chlorine favored hydrogen bonds with topoisomerase 1.

Conclusion: The 3-(acridin-9-ylmethyl)-5-((10-chloroanthracen-9-yl)methylene)thiazolidine-2,4-dione (LPSF/AA-62) presented the most promising results, showing anti-tumor activity in 5 of the 6 cell types tested, especially inhibiting the formation of colonies of prostate tumor cells (DU-145).

Keywords: Acridine, thiazolidine, cancer, medicinal chemistry, cytotoxicity, therapeutic innovation.

[1]
Mali, S.N.; Chaudhari, H.K. Computational studies on imidazo [1,2-a] pyridine-3-carboxamide analogues as antimycobacterial agents: common pharmacophore generation, atom-based 3DQSAR, molecular dynamics simulation, qikprop, molecular docking and prime MMGBSA approaches. Open Pharm. Sci. J., 2018, 5, 12-23.
[http://dx.doi.org/10.2174/1874844901805010012]
[2]
Word Health Organization. Tuberculosis. Available at:. http://www. who.int/topics/tuberculosis/en/
[3]
Angelova, V.T.; Valcheva, V.; Vassilev, N.G.; Buyukliev, R.; Momekov, G.; Dimitrov, I.; Saso, L.; Djukic, M.; Shivachev, B. Antimycobacterial activity of novel hydrazide-hydrazone derivatives with 2H-chromene and coumarin scaffold. Bioorg. Med. Chem. Lett., 2017, 27(2), 223-227.
[http://dx.doi.org/10.1016/j.bmcl.2016.11.071] [PMID: 27914798]
[4]
Lemke, T.L.; Williams, D.A.; Roche, V.F.; Zito, S.W. Foye’s Principles of Medicinal Chemistry, 7th ed; Wolters Kluwer: New Delhi, 2013, p. 1177.
[5]
Bhat, M.A.; Al-Omar, M.A. Synthesis, characterization, and in vitro anti-Mycobacterium tuberculosis activity of terpene Schiff bases. Med. Chem. Res., 2013, 22(9), 4522-4528.
[http://dx.doi.org/10.1007/s00044-012-0458-3]
[6]
Paidi, K.R.; Tatipamula, V.B.; Kolli, M.K.; Pedakotla, V.R. Benzohydrazide incorporated Imidazo [1, 2-b] pyridazine: Synthesis, Characterization and in vitro Anti-tubercular Activity. Int. J. Chem. Sci., 2017, 15(3), 172.
[7]
Tseng, C.H.; Tung, C.W.; Wu, C.H.; Tzeng, C.C.; Chen, Y.H.; Hwang, T.L.; Chen, Y.L. Discovery of indeno [1, 2-c] quinoline derivatives as potent dual antituberculosis and anti-Inflammatory agents. Molecules, 2017, 22(6), 1001.
[http://dx.doi.org/10.3390/molecules22061001] [PMID: 28621733]
[8]
Pavan, F.R.; da S Maia, P.I.; Leite, S.R.; Deflon, V.M.; Batista, A.A.; Sato, D.N.; Franzblau, S.G.; Leite, C.Q. Thiosemicarbazones, semicarbazones, dithiocarbazates and hydrazide/hydrazones: anti-Mycobacterium tuberculosis activity and cytotoxicity. Eur. J. Med. Chem., 2010, 45(5), 1898-1905.
[http://dx.doi.org/10.1016/j.ejmech.2010.01.028] [PMID: 20163897]
[9]
Nusrath Unissa, A.; Hanna, L.E.; Swaminathan, S. A note on derivatives of isoniazid, Rifampicin, and pyrazinamide showing activity against resistant Mycobacterium tuberculosis. Chem. Biol. Drug Des., 2016, 87(4), 537-550.
[http://dx.doi.org/10.1111/cbdd.12684] [PMID: 26613382]
[10]
Sriram, D.; Yogeeswari, P.; Vyas, D.R.K.; Senthilkumar, P.; Bhat, P.; Srividya, M. 5-Nitro-2-furoic acid hydrazones: design, synthesis and in vitro antimycobacterial evaluation against log and starved phase cultures. Bioorg. Med. Chem. Lett., 2010, 20(15), 4313-4316.
[http://dx.doi.org/10.1016/j.bmcl.2010.06.096] [PMID: 20615698]
[11]
Velezheva, V.; Brennan, P.; Ivanov, P.; Kornienko, A.; Lyubimov, S.; Kazarian, K.; Nikonenko, B.; Majorov, K.; Apt, A. Synthesis and antituberculosis activity of indole-pyridine derived hydrazides, hydrazide-hydrazones, and thiosemicarbazones. Bioorg. Med. Chem. Lett., 2016, 26(3), 978-985.
[http://dx.doi.org/10.1016/j.bmcl.2015.12.049] [PMID: 26725953]
[12]
Desale, V.J.; Mali, S.N.; Chaudhari, H.K.; Mali, M.C.; Thorat, B.R.; Yamgar, R.S. Synthesis and Anti-mycobacterium Study of halo-substituted 2-aryloxyacetohydrazones. Curr. Comput. Aided Drug Des., 2019, 15, 1.
[http://dx.doi.org/10.2174/1573409915666191018120611] [PMID: 31648645]
[13]
Coelho, T.S.; Cantos, J.B.; Bispo, M.L.F.; Gonçalves, R.S.B.; Lima, C.H.S.; da Silva, P.E.A.; Souza, M.V. In vitro anti-mycobacterial activity of (E)-N′-(monosubstituted-benzylidene) isonicotinohydrazide derivatives against isoniazid-resistant strains. Infect. Dis. Rep., 2012, 4(1) e13
[http://dx.doi.org/10.4081/idr.2012.e13] [PMID: 24470920]
[14]
de Souza, M.V.N. Promising candidates in clinical trials against multidrug-resistant tuberculosis (MDR-TB) based on natural products. Fitoterapia, 2009, 80(8), 453-460.
[http://dx.doi.org/10.1016/j.fitote.2009.07.010] [PMID: 19698768]
[15]
Smieja, M.J.; Marchetti, C.A.; Cook, D.J.; Smaill, F.M. Isoniazid for preventing tuberculosis in non-HIV infected persons. Cochrane Database Syst. Rev., 2000, (2) CD001363
[http://dx.doi.org/10.1002/14651858.CD001363] [PMID: 10796642]
[16]
Akolo, C.; Adetifa, I.; Shepperd, S.; Volmink, J. Treatment of latent tuberculosis infection in HIV infected persons. Cochrane Database Syst. Rev., 2010, (1) CD000171
[http://dx.doi.org/10.1002/14651858.CD000171.pub3] [PMID: 20091503]
[17]
Schnappinger, D.; Ehrt, S.; Voskuil, M.I.; Liu, Y.; Mangan, J.A.; Monahan, I.M.; Dolganov, G.; Efron, B.; Butcher, P.D.; Nathan, C.; Schoolnik, G.K. Transcriptional adaptation of Mycobacterium tuberculosis within macrophages: Insights into the phagosomal environment. J. Exp. Med., 2003, 198(5), 693-704.
[http://dx.doi.org/10.1084/jem.20030846] [PMID: 12953091]
[18]
Mathew, B.; Suresh, J.; Ahsan, M.J.; Mathew, G.E.; Usman, D.; Subramanyan, P.N.; Safna, K.F.; Maddela, S. Hydrazones as a privileged structural linker in antitubercular agents: a review. Infect. Disord. Drug Targets, 2015, 15(2), 76-88.
[http://dx.doi.org/10.2174/1871526515666150724104411] [PMID: 26205803]
[19]
Belkheiri, N.; Bouguerne, B.; Bedos-Belval, F.; Duran, H.; Bernis, C.; Salvayre, R.; Nègre-Salvayre, A.; Baltas, M. Synthesis and antioxidant activity evaluation of a syringic hydrazones family. Eur. J. Med. Chem., 2010, 45(7), 3019-3026.
[http://dx.doi.org/10.1016/j.ejmech.2010.03.031] [PMID: 20403645]
[20]
Rane, R.A.; Telvekar, V.N. Synthesis and evaluation of novel chloropyrrole molecules designed by molecular hybridization of common pharmacophores as potential antimicrobial agents. Bioorg. Med. Chem. Lett., 2010, 20(19), 5681-5685.
[http://dx.doi.org/10.1016/j.bmcl.2010.08.026] [PMID: 20800487]
[21]
Bawa, S.; Kumar, S.; Drabu, S.; Kumar, R. Synthesis and antimicrobial activity of 2-chloro-6- methylquinoline hydrazone derivatives. J. Pharm. Bioallied Sci., 2009, 1, 27-31.
[http://dx.doi.org/10.4103/0975-7406.62683]
[22]
Kaplancikli, Z.A.; Altintop, M.D.; Özdemir, A.; Turan-Zitounia, G.; Khan, S.I.; Tabanca, N. Synthesis and biological evaluation of some hydrazone derivatives as anti-inflammatory agents. Lett. Drug Des. Discov., 2012, 9, 310-315.
[http://dx.doi.org/10.2174/157018012799129828]
[23]
Hu, W.X.; Zhou, W.; Xia, C.N.; 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]
[24]
Congiu, C.; Onnis, V. Synthesis and biological evaluation of novel acylhydrazone derivatives as potential antitumor agents. Bioorg. Med. Chem., 2013, 21(21), 6592-6599.
[http://dx.doi.org/10.1016/j.bmc.2013.08.026] [PMID: 24071449]
[25]
Vicini, P.; Incerti, M.; La Colla, P.; Loddo, R. Anti-HIV evaluation of benzo[d]isothiazole hydrazones. Eur. J. Med. Chem., 2009, 44(4), 1801-1807.
[http://dx.doi.org/10.1016/j.ejmech.2008.05.030] [PMID: 18614259]
[26]
Rocha, L.T.S.; Costa, K.A.; Oliveira, A.C.P.; Nascimento, E.B., Jr; Bertollo, C.M.; Araújo, F.; Teixeira, L.R.; Andrade, S.P.; Beraldo, H.; Coelho, M.M. Antinociceptive, antiedematogenic and antiangiogenic effects of benzaldehyde semicarbazone. Life Sci., 2006, 79(5), 499-505.
[http://dx.doi.org/10.1016/j.lfs.2006.01.027] [PMID: 16600310]
[27]
Krishnan, K.; Prathiba, K.; Jayaprakash, V.; Basu, A.; Mishra, N.; Zhou, B.; Hu, S.; Yen, Y. Synthesis and ribonucleotide reductase inhibitory activity of thiosemicarbazones. Bioorg. Med. Chem. Lett., 2008, 18(23), 6248-6250.
[http://dx.doi.org/10.1016/j.bmcl.2008.09.097] [PMID: 18976907]
[28]
Thanigaimalai, P.; Lee, K.C.; Sharma, V.K.; Roh, E.; Kim, Y.; Jung, S.H. Ketonethiosemicarbazones: structure-activity relationships for their melanogenesis inhibition. Bioorg. Med. Chem. Lett., 2011, 21(12), 3527-3530.
[http://dx.doi.org/10.1016/j.bmcl.2011.04.146] [PMID: 21601449]
[29]
Brum, J.O.C.; França, T.C.C.; LaPlante, S.R.; Villar, J.D.F. Synthesis and biological activity of hydrazones and derivatives: a review. Mini Rev. Med. Chem., 2020, 20(5), 342-368.
[http://dx.doi.org/10.2174/1389557519666191014142448] [PMID: 31612828]
[30]
Cheng, F.; Li, W.; Zhou, Y.; Shen, J.; Wu, Z.; Liu, G.; Lee, P.W.; Tang, Y. admetSAR: a comprehensive source and free tool for assessment of chemical ADMET properties. J. Chem. Inf. Model., 2012, 52(11), 3099-3105.
[http://dx.doi.org/10.1021/ci300367a] [PMID: 23092397]
[31]
Mali, S.N.; Chaudhari, H.K. Molecular modelling studies on adamantane-based Ebola virus GP-1 inhibitors using docking, pharmacophore and 3D-QSAR. SAR QSAR Environ. Res., 2019, 30(3), 161-180.
[http://dx.doi.org/10.1080/1062936X.2019.1573377] [PMID: 30786763]
[32]
Mali, S.N.; Sawant, S.; Chaudhari, H.K.; Mandewale, M.C. In silico appraisal, Synthesis, Antibacterial screening and DNA cleavage for 1,2,5-thiadiazole derivative. Curr Comput Aided Drug Des, 2019, 15(5), 445-455.
[http://dx.doi.org/10.2174/1573409915666190206142756] [PMID: 30727910]
[33]
Mishra, V.R.; Ghanavatkar, C.W.; Mali, S.N.; Qureshi, S.I.; Chaudhari, H.K.; Sekar, N. Design, synthesis, antimicrobial activity and computational studies of novel azo linked substituted benzimidazole, benzoxazole and benzothiazole derivatives. Comput. Biol. Chem., 2019, 78, 330-337.
[http://dx.doi.org/10.1016/j.compbiolchem.2019.01.003] [PMID: 30639681]
[34]
Mishra, V.R.; Ghanavatkar, C.W.; Mali, S.N.; Chaudhari, H.K.; Sekar, N. Synthesis, bioactivities, DFT and in-silico appraisal of azo clubbed benzothiazole derivatives. J. Mol. Struct., 2019, 1192, 162-171.
[http://dx.doi.org/10.1016/j.molstruc.2019.04.123]
[35]
Mishra, V.R.; Ghanavatkar, C.W.; Mali, S.N.; Chaudhari, H.K.; Sekar, N. Schiff base clubbed benzothiazole: synthesis, potent antimicrobial and MCF-7 anticancer activity, DNA cleavage and computational study. J. Biomol. Struct. Dyn., 2020, 38(6), 1772-1785.
[http://dx.doi.org/10.1080/07391102.2019.1621213] [PMID: 31107179]
[36]
Jadhav, B.S.; Yamgar, R.S.; Kenny, R.S.; Mali, S.N.; Chaudhari, H.K.; Mandewale, M.C. Synthesis, In-Silico and biological studies of thiazolyl-2h-chromen-2-one derivatives as potent antitubercular agents. Curr Comput Aided Drug Des, 2019, 15, 1.
[http://dx.doi.org/10.2174/1386207322666190722162100] [PMID: 31438831]
[37]
Kshatriya, R.; Kambale, D.; Mali, S.N.; Jejurkar, V.P.; Lokhande, P.; Chaudhari, H.K.; Saha, S.S. Brønsted Acid Catalyzed Domino Synthesis of Functionalized 4H‐Chromens and Their ADMET, Molecular Docking and Antibacterial Studies. ChemistrySelect, 2019, 4, 7943-7948.
[38]
Shelke, P.B.; Mali, S.N.; Chaudhari, H.K.; Pratap, A.P. Chitosan hydrochloride mediated efficient, green catalysis for the synthesis of perimidine derivatives. J. Heterocycl. Chem., 2019, 2019
[http://dx.doi.org/10.1002/jhet.3700]
[39]
Kapale, S.S.; Mali, S.N.; Chaudhari, H.K. Molecular modelling studies for 4-oxo-1,4-dihydroquinoline-3-carboxamide derivatives as anticancer agents. Med. Drug Discov., 2019, 2, 100008
[http://dx.doi.org/10.1016/j.medidd.2019.100008]
[40]
Anuse, D.G.; Thorat, B.R.; Sawant, S.; Yamgar, R.S.; Chaudhari, H.K.; Mali, S.N. Synthesis, SAR, Molecular Docking and Anti-Microbial Study of substituted N-bromoamido-2-aminobenzothiazoles. Curr Comput Aided Drug Des, 2019, 15, 1.
[http://dx.doi.org/10.2174/1573409915666190902143648] [PMID: 31475902]
[41]
Jejurkar, V.P.; Mali, S.N.; Kshatriya, R.; Chaudhari, H.K.; Saha, S. Synthesis, antimicrobial screening and in silico appraisal of iminocarbazole derivatives. ChemistrySelect, 2019, 4(32), 9470-9475.
[http://dx.doi.org/10.1002/slct.201901890]
[42]
Abate, G.; Mshana, R.N.; Miörner, H. Evaluation of a colorimetric assay based on 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) for rapid detection of rifampicin resistance in Mycobacterium tuberculosis. Int. J. Tuberc. Lung Dis., 1998, 2(12), 1011-1016.
[PMID: 9869118]
[43]
Anuse, D.G.; Mali, S.N.; Thorat, B.R.; Yamgar, R.S.; Chaudhari, H.K. Synthesis, SAR, In-Silico appraisal and Anti-Microbial Study of substituted 2-aminobenzothiazoles derivatives. Curr. Comput. Aided Drug Des., 2019, 15, 1.
[http://dx.doi.org/10.2174/1573409915666191210125647] [PMID: 31820704]
[44]
Melgari, D.; Zhang, Y.; El Harchi, A.; Dempsey, C.E.; Hancox, J.C. Molecular basis of hERG potassium channel blockade by the class Ic antiarrhythmic flecainide. J. Mol. Cell. Cardiol., 2015, 86, 42-53.
[http://dx.doi.org/10.1016/j.yjmcc.2015.06.021] [PMID: 26159617]
[45]
Cheng, H.; Zhang, Y.; Du, C.; Dempsey, C.E.; Hancox, J.C. High potency inhibition of hERG potassium channels by the sodium-calcium exchange inhibitor KB-R7943. Br. J. Pharmacol., 2012, 165(7), 2260-2273.
[http://dx.doi.org/10.1111/j.1476-5381.2011.01688.x] [PMID: 21950687]
[46]
Raschi, E.; Vasina, V.; Poluzzi, E.; De Ponti, F. The hERG K+ channel: target and antitarget strategies in drug development. Pharmacol. Res., 2008, 57(3), 181-195.
[http://dx.doi.org/10.1016/j.phrs.2008.01.009] [PMID: 18329284]
[47]
Mannhold, R.; Kubinyi, H.; Folkers, G. Antitargets: Prediction and Prevention of Drug Side Effects; John Wiley & Sons, 2008, p. 38.
[48]
Braga, R.C.; Alves, V.M.; Silva, M.F.B.; Muratov, E.; Fourches, D.; Lião, L.M.; Tropsha, A.; Andrade, C.H. Pred-hERG: A novel web-accessible computational tool for predicting cardiac toxicity. Mol. Inform., 2015, 34(10), 698-701.
[http://dx.doi.org/10.1002/minf.201500040] [PMID: 27490970]
[49]
Alves, V.M.; Muratov, E.; Fourches, D.; Strickland, J.; Kleinstreuer, N.; Andrade, C.H.; Tropsha, A. Predicting chemically-induced skin reactions. Part I: QSAR models of skin sensitization and their application to identify potentially hazardous compounds. Toxicol. Appl. Pharmacol., 2015, 284(2), 262-272.
[http://dx.doi.org/10.1016/j.taap.2014.12.014] [PMID: 25560674]
[50]
Alves, V.M.; Muratov, E.; Fourches, D.; Strickland, J.; Kleinstreuer, N.; Andrade, C.H.; Tropsha, A. Predicting chemically-induced skin reactions. Part II: QSAR models of skin permeability and the relationships between skin permeability and skin sensitization. Toxicol. Appl. Pharmacol., 2015, 284, 273-280.
[http://dx.doi.org/10.1016/j.taap.2014.12.013]
[51]
Thorat, B.R.; Rani, D.; Yamgar, R.S.; Mali, S.N. Synthesis, Insilico and In-vitro analysis of hydrazones as potential antituberculosis agents. Curr. Comput. Aided Drug Des., 2020. [epub ahead of print]
[http://dx.doi.org/10.2174/1573409916666200302120942] [PMID: 32141422]

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