3. ATTIVITA’ FARMACOLOGICHE DEI DERIVATI BTA
3.8 BTA COME AGENTI ANTITUBERCOLARI
La tubercolosi (TB), una malattia a lungo considerata sostanzialmente debellata nei paesi sviluppati, è riapparsa drammaticamente negli ultimi decenni, affermandosi come una delle malattie infettive che comporta il maggior numero di decessi umani in tutto il mondo. Probabilmente, la ragione del crescente numero di infezioni con TB patogeno Mycobacterium tubercolosis (Mtb), è la sinergia mortale con il virus HIV, infatti un impressionante numero di individui HIV-infetti soccombe all’aggressione del MT. Ci sono due approcci base per lo sviluppo di nuovi farmaci per la TB: (i) sintesi di analoghi, o derivati di composti esistenti per il trattamento della TB; (ii) ricerca di nuove strutture per il trattamento della resistenza a svariati farmaci usati per la TB[144]. Huangand e collaboratori hanno descritto la sintesi dei derivati BTA-isossazolo- carbossamidici come potenziali antitubercolari e antiprotozoici contro Mtb H37Rv e quattro protozoi parassiti. In particolare i composti (119) e (120) hanno mostrato una potente attività ed un inibizione della crescita di Mtb a concentrazioni micromolari, con valori MIC di 1.4 e 1.9µM, rispettivamente. L’idrossammato (121) mostra una promettente attività contro T.b.rhodesiense. Variazioni a livello del sito amidico sono ben tollerate, con gruppi di dimensioni variabili, dal piccolo gruppo dimetilammino a gruppi come aminoacidi ed esteri [145]. Analoghi coniugati BTA-triazolo-piridina preparati da Rajani e altri, sono stati valutati in vitro per la loro attività anti-tubercolare contro il ceppo Mtb H37Rv. I composti 122(a-d), 122(g-h) e 122(i) hanno mostrato buona attività antimicrobica mentre il composto 122(j) ha presentato migliore attività anti-TB rispetto alla Rifampicina (RIF). I composti che hanno come sostituenti alogeni, metili e nitro possiedono un promettente potenziale antibatterico, gli analoghi sostituenti con metili mostrano miglior attività antifungina [146]. Altri esempi sono dati dai derivati benzotiazolo-naftiridonici, valutati in vivo ed in vitro per la loro attività anti-
62 TB contro Mtb H37Rv e MDR-TB (una forma di TB resistente ai farmaci). Il composto
(123) si è mostrato il più attivo in vitro con MIC=0.19 e 0.04 µM contro Mtb e MTR-TB
rispettivamente; inoltre presenta una promettente attività contro MDR-TB, 208 e 1137 volte più potente in confronto a Glatifloxacina e Isoniazide (INH), rispettivamente. Nel modello animale in vivo (123), il carico di micobatteri nei tessuti polmonari risulta diminuito con protezioni di 2.81 e 4.94-log10, rispettivamente, ad una dose di 50 mg/kg di peso corporeo. Gli analoghi piperidina-sostituiti hanno mostrano maggior attività anti-TB ed una buona ci tossicità [147]. I derivati BTA-ureici e tioureici sono stati preparati da Abdel-Rahman e altri, e valutati in vivo per la loro citotossicità, per l’attività anti-TB e antimicrobica, contro le cellule del cancro al seno MCF-7 e contro MtbH37Rv, E.coli, S.aureus e C.albicans. Il composto (124a) mostra attività anti-TB e un effettiva azione sulle linee cellulari di cancro al seno MCF-7 (37% di inibizione della crescita). Il composto (124b) rivela buona attività microbica contro E.coli mentre (124c) è attivo contro S.aureus, similmente all’ Ampicillina [148]. I derivati BTA che hanno sostituenti difenil eterei sono stati studiati contro Mtb H37Rv. Composti con alogeni sull’anello BTA del 2-(2-(4-arilossibenzilidene)idrazinil)benzotiazolo, mostrano buona attività anti-TB mentre l‘introduzione di un gruppo metile, metossi e nitro in posizione 6 sul BTA, diminuiscono l’attività [149].
N S C H3 O O N N H O O O CH3 (119)
63 N S C H3 O O N N H O O O CH3 (120) N S C H3 O O N N H O O N H OH (121) N N N N NH CH3 N S R
(122 a-j) R= a) 6-F, b) 6-Br, c) 6-NO2, d) 6-CH3, e) 6-OCH3, f) 6-Cl, g) 4-CH3, h) 4-NO2, i) 5,6-Cl, j) 4-Cl
64 N N N S N O O O2N O O OH N O O (123) S N NH NH N O O S N N H N H N H N H N H S O O (124a) (124b) S N NH NH N H NH2 S O (124c)
I coniugati benzimidazolo-ossidazolo-BTA mostrano buona attività anti-TB contro Mtb H37Rv. I composti (125) e (126)che hanno rispettivamente come sostituente un fluoro e un metossi sul BTA mostrano 12.5µg/mL di MIC (concentrazione inibitoria minima) contro Mtb H37 Rv. La presenza di alogeni, sostituenti alcossi e ciano migliora la potenza anti-tubercolare [150]. I regioisomeri fluoronitrobenzotiazolo-pirazolina sono stati sintetizzati e saggiati in vitro per la loro attività anti-TB contro il ceppo MtbH37Rv. I composti 127(a-c) hanno esibito il 100% di inibizione a 25µg/mL rispetto al farmaco standard streptomicina che mostra il 100% di inibizione a 7.5µg/mL. Composti aventi un gruppo nitro in posizione 5 dell’anello BTA mostrano una migliore attività antitubercolare rispetto ai composti non sostituiti sul BTA. Sostituenti elettron-donatori nell’anello aromatico migliorano l’attività anti-TB [152]. I coniugati 2- mercaptobenzotiazolici e triazolici sono stati valutati per la loro attività anti-TB contro
65 il ceppo MtbH37Rv a concentrazioni di 8µg/mL. Dagli studi di SAR, si evidenzia che la sostituzione con un cloro e un nitro sull’anello aromatico potenzia l’attività [153].
N N N N O S N H O N S F (125) N N N N O S N H O N S O CH3 (126) N S N N NH S N F Cl F O2N Cl R (127 a-c)
66
4.CONCLUSIONE
Le precedenti discussione mostrano chiaramente come la struttura dell’ anello benzotiazolico giochi un importante ruolo nella chimica medicinale e la ricerca correlata ha portato a composti attivi. Una grande quantità di lavoro è stato fatto verso la chimica medicinale basata sui BTA. Numerosi risultati eccezionali hanno rivelato che i composti con base BTA possiedono ampie e potenziali applicazioni come farmaci medicinali e agenti diagnostici. In particolare, un grande numero di composti basati sui BTA come clinici agenti antitumorali, antibatterici, antifungini, antinfiammatori, analgesici, anti- HIV, antiossidanti, anti convulsivanti, antitubercolari, antidiabetici, antileishmaniosi e antistaminici sono stati sviluppati con successo, commercializzati e ampiamente usati nella clinica, nella prevenzione e nel trattamento di vari tipi di malattie con bassa tossicità, alta biodisponibilità, buona biocompatibilità ed effetti curativi. Tutto questo ha suggerito l’infinita potenzialità dei derivati BTA nel campo della medicina. Un crescente numero di derivati BTA sta diventando importante come farmaci clinici
candidati in modo attivo nella ricerca e nello sviluppo. C’è ancora molto spazio in questa promettente porzione come un numero di diversi
bersagli molecolari, indagini future di questo scaffold può dare risultati più incoraggianti nel campo medico. Si prevede che questa informazione potrebbe dare luogo a molecole migliori con maggiori proprietà biologiche e maggiore specificità, assieme allo sviluppo di nuove strategie di sintesi.
67
5.BIBLIOGRAFIE
[1] G.P. Gunawardana, S. Kohmoto, S.P. Gunesakara, O.J. McConnel, F.E. Koehn, Dercitine, a new biologically active acridine alkaloid from a deep water
marine sponge, Dercitus sp, J. Am. Chem. Soc. 110 (1988) 4856 e 4858.
[2] G.P. Gunawardana, S. Kohmoto, N.S. Burres, New cytotoxic acridine alkaloids from two deep water marine sponges of the family Pachastrellidae, Tetrahedron Lett. 30 (1989) 4359 e 4362.
[3] S.T. Huang, I.J. Hsei, C. Chen, Synthesis and anticancer evaluation of bis(- benzimidazoles), bis(benzoxazoles), and benzothiazoles, Bioorg. Med. Chem. 14 (2006) 6106 e 6119.
[4] M. Singh, S.K. Singh, M. Gangwar, G. Nath, S.K. Singh, Design, synthesis and mode of action of some benzothiazole derivatives bearing an amide moiety
as antibacterial agents, RSC Adv. 4 (2014) 19013 e 19023.
[5] N. Siddiqui, S.N. Pandeya, S.A. Khau, J. Stables, A. Rana, M. Alam, F. MdArshad, M.A. Bhat, Synthesis and anticonvulsant activity of sulfonamide
derivativeshydrophobic domain, Bioorg. Med. Chem. 17 (2007) 255 e 259.
[6] T. Akhtar, S. Hameed, N. Al-Masoudi, R. Loddo, P. Colla, In vitro antitumor and antiviral activities of new benzothiazole and 1,3,4-oxadiazole-2-thione derivatives, Acta Pharm. 58 (2008) 135 e 149.
[7] F.J. Palmer, R.B. Trigg, J.V. Warrington, Benzothiazolines as antituberculous agent, J. Med. Chem. 14 (1971) 248 e 251.
[8] A. Burger, S.N. Sawhey, Antimalarials. III. Benzothiazole amino alcohols, J. Med. Chem. 11 (1968) 270 e 273.
[9] C.H. Suresh, J.V. Rao, K.N. Jayaveera, S.K. Subudhi, Synthesis and anthelmintic activity of 3-(2-hydrozino benzothiazole)-substituted indole-2-one, Int,
J. Pharma.2 (2013) 257 e 261.
[10] N. Siddiqui, M. Alam, A.A. Siddiqui, Synthesis and analgesic activity of some 2-[{4-(alkyl thioureido) phenyl} sulphonamido]-6-substituted benzothiazoles, Asian J. Chem. 16 (2004) 1005 e 1008.
[11] B.M. Gurupadayya, M. Gopal, B. Padmashali, V.P. Vaidya, Synthesis and bological activities of fuorobenzothiazoles, Ind. J. Heterocy Chem. 15 (2005) 169 e 172.
[12] S.R. Pattan, Ch Suresh, V.D. Pujar, V.V.K. Reddy, V.P. Rasal, B.C. Koti, Synthesis
and antidiabetic activity of 2-amino [50(4-sulphonylbenzylidene-2,4- thiazolidenedinone]-7-chloro-6-flourobenzothiazole, Ind. J. Chem. 44B (2005) 2404 e 2408.
68 [13] S.P. Singh, S. Segal, Study of fungicidal activities of some benzothiazoles, Ind. J. Chem. 27B (1988) 941 e 943.
[14] G. Henriksen, A.I. Hauser, A.D. Westwell, B.H. Yousefi, M. Schwaiger, A. Drzega, H.J. Wester, Metabolically stabilized benzothiazoles for imaging of amyloid plaques, J. Med. Chem. 50 (2007) 1087 e 1089.
[15] C.A. Mathis, Y. Wang, D.P. Holt, G.F. Haung, M.L. Debnath, W.E. Klunk, Synthesis and evaluation of 11C-labeled 6-substituted 2-arylbenzothiazoles as amyloid imaging agents, J. Med. Chem. 46 (2003) 2740 e 2754.
[16] X. Wang, K. Sarris, K. Kage, D. Zhang, S.P. Brown, T. Kolasa, C. Surowy, O.F. ElKouhen, S.W. Muchmore, J.D. Brioni, A.O. Stewart, Synthesis and evaluation of benzothiazole-based analogues as novel, potent, and selective fatty acid amide hydrolase inhibitors, J. Med. Chem. 52 (2009) 170 e 180.
[17] C. Black, D. Deschenes, M. Gagnon, N. Lachance, Y. Leblanc, S. Leger, C.S. Li, R.M. Oballa, PCT Int Appl. 2006; WO 2006122200 A1 20061116.
[18] C.K. Lau, C. Dufresne, Y. Gareau, R. Zamboni, M. Labelle, R.N. Young, K.M. Metters, C. Rochette, N. Sawyer, D.M.L. Slipetz, C.T. Jones, M. McAuliffe, C. McFarlane, A.W. Ford-Hutchinson, Evolution of a series of non-quinoline leukotriene D4 receptor antagonist; synthesis and sar of benzothiazoles and thiazoles substituted benzyl alcohols as potent LTD4 antagonists, Bioorg. Med. Chem. 5 (1995) 1615 e 1620.
[19] J.M. Bergman, P.J. Coleman, C. Cox, G.D.C. Hartman Lindsley, S.P. Mercer, A.J. Roecker, D.B. Whitman.2,5-Disubstituted piperidine orexin receptor antagonists, PCT Int. Appl (2006). WO 2006127550.
[20] J. Apelt, S. Grassmann, X. Ligneau, H.H. Pertz, C.R. Ganellin, J.M. Arrang, J.C. Schwartz, W. Schunack, H. Stark, Search for histamine H3 receptor antagonists with combined inhibitory potency at N-tau-methyltransferase:
ether derivatives, Pharmazie 60 (2005) 97 e 106.
[21] A.C. Razus, L. Birzan, N.M. Surugiu, A.C. Corbu, F. Chiraleu, Syntheses of azulen-1-yl-benzothiazol-2-yl aiazenes, Dyes Pigments 74 (2007) 26 e 33. [22] T. Papenfuh, Preparation of benzothiazoles as intermediates for dyes, plant protectants and pharmaceuticals, Ger. Pat. 3 (1987), 528-332.
[23] R.L. Parton, D.A. Stegman, K.W. Williams, V.L. Chand, Benzothiazole, benzoselenazole or benzooxazole sensitizers for photographic films, 1995, US5516628 A.
[24] H. Kokelenberg, C.S. Marve, Polymers containing anthraquinone units: benzimidazole and benzothiazole polymers, J. Polym. Sci. A Polym. Chem. 8 (1970) 3199 e 3209.
69 [25] Z. Cao, F. Qiu, Q. Wang, G. Cao, L. Zhuang, Q. Shen, X. Xu, J. Wang, Q. Chen, D. Yang, Synthesis of azo benzothiazole polymer and its application of 1 _ 2
Y-branched and 2 _ 2 MacheZehnder interferometer switch, Optik-Int J. Light Elec. Opt. 124 (2013) 4036 e 4040.
[26] K.W. Seo, M. Park, J.G. Kim, T.W. Kim, H.J. Kim, Effects of benzothiazole on the xenobiotic metabolizing enzymes and metabolism of acetaminophen, J. Appl.
Toxicol. 20 (2000) 427 e 430.
[27] T. Reemtsma, O. Fiehn, G. Kalnowski, M. Jekel, Microbial transformations and biological effects of fungicide-derived benzothiazoles determined in industrial waste water, Environ. Sci. Technol. 29 (1995) 478 e 485.
[28] a) D. Hartley, H. Kidd, The Agrochemical Handbook, The Royal Society of Chemistry, Nottingham, United Kingdom, 1987;
b) R. Wegler, L. Eue, Chemie der Pflanzenschutz- und
Sch€adlingsbek€ampfungsmittel, in: Herbizide, vol. 5, Springer-Verlag, Berlin, Germany, 1977.
[29] B. Meding, K. Toren, A.T. Karlberg, S. Hagberg, K. Wass, Evaluation of skin symptoms among workers at a Swedish paper mill, Am. J. Ind. Med. 23
(1993) 720 e 728.
[30] A.T. Peters, S.S. Yang, Monoazo disperse dyes derived from nitro-2- aminobenzothiazoles, Dyes Pigments 28 (1995) 151 e 164.
[31] http://www.drugs.com/pro/rilutek.html.
[32] a) D.F. Shi, T.D. Bradshaw, S. Wrigley, C.J. McCall, P. Lelieveld, I. Fichtner, M.F. Stevens, Antitumor benzothiazoles 3. Synthesis of 2-(4-aminophenyl)
benzothiazoles and evaluation of their activities against breast cancer cell lines in vitro and in vivo, J. Med. Chem. 39 (1996) 3375e3384;
b) I. Hutchinson, S.A. Jennings, B.R. Vishnuvajjala, A.D. Westwell, M.F. Stevens, Antitumor benzothiazoles 16. Synthesis and pharmaceutical properties of antitumor 2-(4-aminophenyl)benzothiazole amino acid prodrugs, J. Med. Chem. 45 (2002) 744 e 747.
[33] a) O. Fiehn, T. Reemtsma, M. Jekel, Extraction and analysis of various benzothiazoles from industrial wastewater, Anal. Chim. Acta 295 (1994) 297e305;
b) T. Reemtsma, Determination of 2-substituted benzothiazoles of industrial use from water by liquid chromatography/electrospray ionization tandem mass spectrometry, Rapid Commun. Mass Spectrom. 14 (2000) 1612 e 1618. [34] La Placa, 2005, Principi di Microbiologia Medica, Decima Ed.
[35] Davis Bernard D., Dulbecco Renato, Eisen Hermann N., Ginsebrg Harold S., 1993, Microbiologia, 4a edizione
70 [37] Patric R. Murray, 2008, Microbiologia Medica, Quinta Ed.
[38] TS. Walsh, DM. Dixon, Deep Mycoses in Baron S et al. eds., Baron’s Medical
Microbiology, 4th, Univ of Texas Medical Branch, 1996.
[39] C. Denfert, B. Hube, Candida: genomica, comparativa e funzionale, Caister Academic Press, 2007, ISBN, pp. 4-13.
[40] D. Kruszewska, H.G. Sahl, G. Bierbaum, U. Pag, S.O. Hynes, A. Ljungh,
Mersacidin eradicates methicillin-resistant Staphylococcus aureus (MRSA) in a mouse rhinitis model, J. Antimicrob. Chemother. 54 (2004) 648 e 653.
[41] H. Bujdakova, M. Muckova, Antifungal activity of a new benzothiazole derivative against Candida in vitro and in vivo, Int. J. Antimicrob. Agents 4 (1994) 303 e 308. [42] B. Soni, M.S. Ranawat, R. Sharma, A. Bhandari, S. Sharma, Synthesis and
evaluation of some new benzothiazole derivatives as potential antimicrobial agents, Eur. J. Med. Chem. 45 (2010) 2938 e 2942. [43] I. Argyropoulou, A. Geronikaki, P. Vicini, F. Zani, Synthesis and biological evaluation of sulfonamide thiazole and benzothiazole derivatives as antimicrobial agents, ARKIVOC 6 (2009) 89 e 102.
[44] P. Sharma, M. Kumar, V. Mohan, Synthesis and antimicrobial activity of 2Hpyrimido[2,1-b]benzothiazol-2-ones, Res. Chem. Intermed. 36 (2010) 985 e 993.
[45] A. Pandurangan, A. Sharma, N. Sharma, P.K. Sharma, S. Visht, Synthesis and structural studies of novel benzothiazole derivative and evaluation of their
antimicrobial activity, Der Pharma Chem. 2 (2010) 316 e 324.
[46] S. Saeed, N. Rashid, P.G. Jones, M. Ali, R. Hussain, Synthesis, characterization and biological evaluation of some thiourea derivatives bearing benzothiazole
moiety as potential antimicrobial and anticancer agents, Eur. J. Med. Chem. 45 (2010) 1323 e 1331.
[47] A.M. Youssef, E. Noaman, Synthesis and evaluation of some novel benzothiazole derivatives as potential anticancer and antimicrobial agents, Arzneim.
57 (2007) 547 e 553.
[48] A.J. Rao, P.V. Rao, V.K. Rao, C. Mohan, C.N. Raju, C. Suresh Reddy, Microwave assisted one-pot synthesis of novel a-aminophosphonates and their biological
activity, Bull. Korean Chem. Soc. 31 (2010) 1863 e 1868.
[49] M.K. Singh, R. Tilak, G. Nath, S.K. Awasthi, A. Agarwal, Design, synthesis and antimicrobial activity of novel benzothiazole analogs, Eur. J. Med. Chem. 63
71 [50] N.B. Patel, A.C. Purohit, D.P. Rajani, R. Moo-Puc, G. River, New 2-
benzylsulfanyl-nicotinic acid based 1,3,4-oxadiazoles: their synthesis and biological evaluation, Eur. J. Med. Chem. 62 (2013) 677 e 687.
[51] P. Bandyopadhyay, M. Sathe, S. Ponmariappan, A. Sharma, P. Sharma, A.K. Srivastava, M.P. Kaushik, Exploration of in vitro time point quantitative evaluation of newly synthesized benzimidazole and benzothiazole derivatives as potential antibacterial agents, Bioorg. Med. Chem. Lett. 21 (2011)
7306 e 7309.
[52] A. Catalano, A. Carocci, I. Defrenza, M. Muraglia, A. Carrieri, F.V. Bambeke, A. Rosato, F. Corbo, C. Franchini, 2-Aminobenzothiazole derivatives: search for new antifungal agents, Eur. J. Med. Chem. 64 (2013) 357 e 364.
[53] J.A. Modi, K.C. Patel, Design, synthesis of some 2,6,9-trisubstituted purinyl thioureido derivatives and evaluation of antimicrobial activity, Med. Chem. Res. 21 (2012) 1660 e 1664.
[54] M. Amir, S.A. Javed, M.Z. Hassan, Synthesis and antimicrobial activity of pyrazolinones and pyrazoles having benzothiazole moiety, Med. Chem. Res. 21 (2012) 1261 e 1270.
[55] K. Bolelli, I. Yalcin, T. Ertan-Bolelli, S. Ozgen, F. Kaynak-Onurdag, I. Yildiz, E. Aki, Synthesis of novel 2-[4-(4- substitutedbenzamido/phenylacetamido)
phenyl]benzothiazoles as antimicrobial agents, Med. Chem. Res. 21 (2012) 3818 e 3825.
[56] P. Patel, J. Pillai, N. Darji, P. Patel, B. Patel, Design, synthesis and characterization of novel molecules comprising benzothiazole and sulphonamide
linked to substituted aryl group via azo link as potent antimicrobial agents, Int. J. Drug Res. Tech. 2 (2012) 289 e 296.
[57] P.P. Prabhu, C.S. Shastry, S.S. Pande, T. Panneer Selvam, Design, synthesis, characterization and biological evaluation of benzothiazole-6-carboxylate
derivatives, Res. Pharma 1 (2011) 6 e 12.
[58] C. Franchini, M. Muraglia, F. Corbo, M.A. Florio, A.D. Mola, A. Rosato, R. Matucci, M. Nesi, F. Bambeke, C. Vitali, Synthesis and biological evaluation of 2-mercapto-1,3-benzothiazole derivatives with potential antimicrobial
activity, Arch. Pharm. Chem. Life Sci. 342 (2009) 605 e 613.
[59] P. Venkatesh, V.S. Tiwari, Design and synthesis of Quinazolinone, benzothiazole derivatives bearing guanidinopropanoic acid moiety and their Schiff
bases as cytotoxic and antimicrobial agents, Arab. J. Chem. (2014), http:// dx.doi.org/10.1016/j.arabjc.2011.09.004 (in press).
[60] S. Maddila, S. Gorle, N. Seshadri, P. Lavanya, S.B. Jonnalagadd, Synthesis, antibacterial and antifungal activity of novel benzothiazole pyrimidine derivatives, Arab. J. Chem. (2014), http://dx.doi.org/10.1016/
72 [61] N.B. Patel, I.H. Khan, S.D. Rajani, Antimycobacterial and antimicrobial study of new 1,2,4-triazoles with benzothiazoles, Arch. Pharm. Chem. Life Sci. 10 (2010) 692 e 699.
[62] H. Bhatt, S. Sharma, 2-(5-Chlorobenzo[d]thiazol-2-ylimino)thiazolidin-4-one derivatives as an antimicrobial agent, Arab. J. Chem. (2014), http://
dx.doi.org/10.1016/j.arabjc.2012.10.015 (in press).
[63] S. Bondock, W. Fadaly, M.A. Metwally, Synthesis and antimicrobial activity of some new thiazole, thiophene and pyrazole derivatives containing benzothiazole moiety, Eur. J. Med. Chem. 45 (2010) 3692 e 3701.
[64] Y. Gupta, V. Gupta, S. Singh, Synthesis, characterization and antimicrobial activity of pyrimidine based derivatives, J. Pharma.Res. 7 (2013) 491 e 495.
[65] P. Anand, A.B. Kunnumakara, C. Sundaram, K.B. Harikumar, S.T. Tharakan, O.S. Lai, B. Sung, B.B Aggarwal, Cancer is a preventable disease that requires major
lifestyle changes, vol 25, n 9, settembre 2008, pp.2097-116.
[66,67] V.Kumar, A.K. Abbas, N. Fausto, Le basi patologiche delle malattie-Patologia generale, 7a edizione, Elsevier.
[68] S.J. Choi, H.J. Park, S.K. Lee, S.W. Kim, G. Han, H.Y.P. Choo, Solid phase combinatorial synthesis of benzothiazoles and evaluation of topoisomerase II inhibitory activity, Bioorg. Med. Chem. 14 (2006) 1229 e 1235.
[69] C.K. Ozen, B.T. Gulbas, E. Foto, I. Yildiz, N. Diril, E. Aki, I. Yalcin,
Benzothiazole derivatives as human DNA topoisomerase IIa Inhibitors, Med. Chem. Res. 22 (2013) 5798 e 5808.
[70] A. Pinar, P. Yurdakul, I. Yildiz, O. Temiz-Arpaci, N. Leyla Acan, E. Aki-Sener, I. Yalcin, Some fused heterocyclic compounds as eukaryotic topoisomerase II inhibitors, Biochem. Bioph. Res. Comm. 317 (2004) 670 e 674.
[71] M. Abdel-Aziz, K. Matsuda, M. Otsuka, M. Uyeda, T. Okawara, K. Suzuki, Inhibitory activities against topoisomerase I & II by polyhydroxybenzoyl amide
derivatives and their structure-activity relationship, Bioorg. Med. Chem. Lett. 14 (2004) 1669 e 1672.
[72] E. Pasquier, M. Kavallaris, Microtubules: a dynamic target in cancer therapy, IUBMB Life 60 (2008) 165 e 170.
[73] M. Kavallaris, Microtubules and resistance to tubulin-binding agents, Nat. Rev. Cancer 10 (2010) 194 e 204.
73 [74] B. Bhattacharyya, D. Panda, S. Gupta, M. Banerjee, Antimitotic activity of
colchicine and the structural basis for its interaction with tubulin, Med. Res. Rev. 28 (2008) 155 e 183.
[75] S. Arora, X.I. Wang, S.M. Keenan, C. Andaya, Q. Zhang, Y.Y. Peng, W.J. Welsh, Novel microtubule polymerization inhibitor with potent antiproliferative and antitumor activity, Cancer Res. 69 (2009) 1910 e 1915.
[76] K. Bonezzi, G. Taraboletti, P. Borsotti, F. Bellina, R. Rossi, R. Giavazzi, Vascular disrupting activity of tubulin-binding 1,5-diaryl-1H-imidazoles, J. Med. Chem. 52 (2009) 7906 e 7910.
[77] A. Ciupa, N.J. Griffiths, S.K. Light, P.J. Wood, L. Caggiano, Design, synthesis and antiproliferative activity of urocanic-chalcone hybrid derivatives, Med- ChemComm 2 (2011) 1011 e 1015.
[78] A. Kamal, A. Mallareddy, P. Suresh, T.B. Shaik, V.L. Nayak, C. Kishor, R. Shetti, N.S. Rao, J.R. Tamboli, S. Ramakrishna, A. Addlagatta, Synthesis of
chalconeamidobenzothiazole conjugates as antimitotic and apoptotic inducing agents, Bioorg. Med. Chem. 20 (2012) 3480 e 3492.
[79] A. Kamal, C. Ratna Reddy, S. Prabhakar, 2-Phenyl benzothiazole linked imidazole compounds as potential anticancer agents, WO 2012110959 A1.
[80] P. Danielson, The cytochrome P450 superfamily: biochemistry, evolution and drug metabolism in humans in Curr Drug Metab, vol 3, n 6, 2002, pp.561-97.
[81] A. Parkinson, An overview of current cytochrome P450 technology for assessing the safety and efficacy of new materials in Toxicol Pathol, vol 24, 1996, pp.45-57. [82] I. Hutchinson, M. Chua, H.L. Browne, V. Trapani, T.D. Bradshaw, A.D. Westwell, M.F.G. Stevens, Antitumor benzothiazoles. 14.1 Synthesis and in nitro biological properties of fluorinated 2-(4-aminophenyl)benzothiazoles, J. Med. Chem. 44 (2001) 1446 e 1455.
[83] E. Kashiyama, I. Hutchinson, M. Chua, S.F. Stinson, L.R. Phillips, G. Kaur, E.A. Sausville, T.D. Bradshaw, A.D. Westwell, M.F.G. Stevens, Antitumor benzothiazoles. 8.1 Synthesis, metabolic formation, and biological properties of the C- and N-Oxidation products of antitumor 2-(4-aminophenyl)-benzothiazoles, J. Med. Chem. 42 (1999) 4172 e 4184.
[84] A. Kamal, M.N.A. Khan, K. Srinivasa Reddy, Y.V.V. Srikanth, B. Sridhar, Synthesis,
structural characterization and biological evaluation of novel [1,2,4]
triazolo[1,5-b][1,2,4]benzothiadiazine-benzothiazole conjugates as potential anticancer agents, Chem. Biol. Drug Des. 71 (2008) 78 e 86.
74 Synthesis and anticancer activity evaluation of 4-thiazolidinones containing
benzothiazole moiety, Eur. J. Med. Chem. 45 (2010) 5012 e 5021.
[86] L. Jin, B. Song, G. Zhang, R. Xu, S. Zhang, X. Gao, D. Hu, S. Yang, Synthesis, Xray crystallographic analysis,and antitumor activity of N-(benzothiazole-2-
yl)-1-(fluorophenyl)-O,O-dialkyl-a-aminophosphonates, Bioorg. Med. Chem. Lett. 16 (2006) 1537 e 1543.
[87] Z. Wang, X. Shi, J. Wang, T. Zhou, Y. Xu, T. Huang, Y. Li, Y. Zhao, L. Yang, S. Yang, L. Yu, Y. Wei, Synthesis, structure-activity relationships and preliminary antitumor evaluation of benzothiazole-2-thiol derivatives as novel
apoptosis inducers, Bioorg. Med. Chem. Lett. 21 (2011) 1097 e 1101.
[88] S.N. Manjula, N.M. Noolvi, K.V. Parihar, S.A. Manohara Reddy, V. Ramani, A.K. Gadad, G. Singh, N.G. Kutty, C.M. Rao, Synthesis and antitumor activity of optically active thiourea and their 2-aminobenzothiazole derivatives: a
novel class of anticancer agents, Eur. J. Med. Chem. 44 (2009) 2923 e 2929. [89] A. Kamal, J.R. Tamboli, V.L. Nayak, S.F. Adil, M.V.P.S. Vishnuvardhan, S. Ramakrishna, Synthesis of pyrazolo[1,5-a]pyrimidine linked aminobenzothiazole conjugates as potential anticancer agents, Bioorg. Med. Chem.
Lett. 23 (2013) 3208 e 3215.
[90] R.M. Kumbhare, U.B. Kosurkar, M.J. Ramaiah, T.L. Dadmal,
S.N.C.V.L. Pushpavalli, M. Pal-Bhadra, Synthesis and biological evaluation of novel triazoles and isoxazoles linked 2-phenyl benzothiazole as potential anticancer agents, Bioorg. Med. Chem. Lett. 22 (2012) 5424 e 5427.
[91] D.T.K. Oanh, H.V. Hai, S.H. Park, H. Kim, B.W. Han, H.S. Kim, J.T. Hong, S.B. Han, V.T.M. Hue, N.H. Nam, Benzothiazole-containing hydroxamic acids as histone deacetylase inhibitors and antitumor agents, Bioorg. Med. Chem. Lett. 21 (2011) 7509 e 7512.
[92] J. Cai, M. Sun, X. Wu, J. Chen, P. Wang, X. Zong, M. Ji, Design and synthesis of novel 4-benzothiazole amino quinazolines dasatinib derivatives as potential
antitumor agents, Eur. J. Med. Chem. 63 (2013) 702 e 712.
[93] R.R. Reis, E.C. Azevedo, M.C.B.V. Souza, V.F. Ferreira, R.C. Montenegro, A.J. Araújo, C. Pessoa, L.V. Costa-Lotufo, M.O. Moraes, J.D.B.M. Filho, A.M.T. de Souza, N.C. de Carvalho, H.C. Castro, C.R. Rodrigues, T.R.A. Vasconcelos,
Synthesis and anticancer activities of some novel 2-(benzo[d]thiazol-2-yl)-8- substituted-2H-pyrazolo[4,3-c]quinolin-3(5H)-ones, Eur. J. Med. Chem. 46 (2011) 1448 e 1452.
[94] M.N. Noolvi, H.M. Patel, M. Kaur, Benzothiazoles: search for anticancer agents, Eur. J. Med. Chem. 54 (2012) 447 e 462.
75 [95] A. Kamal, S. Faazil, M.J. Ramaiah, M. Ashraf, M. Balakrishna,
S.N.C.V.L. Pushpavalli, N. Patel, M. Pal-Bhadra, Synthesis and study of benzothiazole conjugates in the control of cell proliferation by modulating Ras/
MEK/ERK-dependent pathway in MCF-7 cells, Bioorg. Med. Chem. Lett. 23 (2013) 5733 e 5739.
[96] M.A. Abdelgawad, A. Belal, H.A. Omar, L. Hegazy, M.E. Rateb, Synthesis, antibreast cancer activity, and molecular modeling of some benzothiazole
and benzoxazole derivatives, Arch. Pharm. Chem. Life Sci. 346 (2013) 534 e 541.
[97] S.L. Rogers, M.R. Farlow, R.S. Doody, R. Mohs, L.T. Friedhoff, Neurology 50 (1998) 136.
[98] J.L. Cummings, Cholinesterase inhibitors: a new class of psychotropic agents, Am. J. Psychiatry 157 (2000) 4 e 15.
[99] R.S. Keri, C. Quintanova, S.M. Marques, A.R. Esteves, S.M. Cardoso, M.A. Santos, Design, synthesis and neuroprotective evaluation of novel
tacrine-benzothiazole hybrids as multi-targeted compounds against Alzheimer's disease, Bioorg. Med. Chem. 21 (2013) 4559 e 4569.
[100] L. Huang, T. Su, W. Shan, Z. Luo, Y. Sun, F. He, X. Li, Inhibition of
cholinesterase activity and amyloid aggregation by berberine-phenylbenzoheterocyclic and tacrine-phenylbenzoheterocyclic hybrids, Bioorg. Med. Chem. 20 (2012) 3038 e 3048.
[101] A. Imramovsky, V. Pejchal, S. Stepankova, K. Vorcakova, J. Jampilek, J. Vanco, P. Simunek, K. Kralovec, L. Bru_ckova, J. Mandikova, F. Trejtnar, Synthesis and in vitro evaluation of new derivatives of 2-substituted-6-fluorobenzo[d]
thiazoles as cholinesterase inhibitors, Bioorg. Med. Chem. 21 (2013) 1735 e 1748.
[102] J.M. Alvaro-Gracia, Licofelone-clinical update on a novel LOX/COX inhibitor for the treatment of osteoarthritis, Rheumatology 43 (2004) 121 e 125.
[103] H. Kaur, S. Kumar, I. Singh, K.K. Saxena, A. Kumar, Synthesis, characterization and biological activity of various substituted benzothiazole derivatives, Dig.
J. Nanomater. Bios 5 (2010) 67 e 76.
[104] M. Srivastav, M. Salahuddin, S.M. Shantakumar, Synthesis and antiinflammatory activity of some novel 3-(6-substituted-1, 3-benzothiazole-2-
yl)-2-[{(4-substituted phenyl) amino} methyl]quinazolines-4 (3H)-ones, E-J Chem. 6 (2009) 1055 e 1062.
[105] D.S. Bele, I. Singhvi, Synthesis, analgesic and antiinflammatory activity of some mannich bases of 6-substituted-2-aminobenzothiazole, Inter. J. Comp. Pharma 10 (2010) 1 e 5.
76 [106] C.H. Suresh, J. Venkateshwara Rao, K.N. Jayaveera, Anti inflammatory activity of 3-(2-hydrazino benzothiazoles) -substituted indole-2-one, Inter. J. Comp.
Pharma Pharma. Sci. Res. 1 (2011) 30 e 34.
[107] S. Shafi, M.M. Alam, N. Mulakayala, C. Mulakayala, G.A.M. Vanaja, Kalle, R. Pallu, M.S. Alam, Synthesis of novel 2-mercapto benzothiazole and 1,2,3- triazole based bis-heterocycles: their antiinflammatory and antinociceptive activities, Eur. J. Med. Chem. 49 (2012) 324 e 333.
[108] S.J. Gilani, S.A. Khan, Synthesis and pharmacological evaluation of N-(6- chlorobenzo[d]thiazol-2-yl)hydrazine carboxamide derivatives of benzothiazole, Med. Chem. Res. 22 (2013) 3316 e 3328.
[109] A. Santhoshi, B. Mahendar, S. Mattapally, P.S. Sadhu, S.K. Banerjee, V.J. Rao, Synthesis of thio-heterocyclic analogues from Baylis-Hillman bromides as
potent cyclooxygenase-2 inhibitors, Bioorg. Med. Chem. Lett. 24 (2014) 1952 e 1957.
[110] R. Paramashivappa, P. Phani Kumar, P.V. Subba Rao, A. Srinivasa Rao, Design, synthesis and biological evaluation of benzimidazole/benzothiazole and
benzoxazole derivatives as cyclooxygenase inhibitors, Bioorg. Med. Chem. Lett. 13 (2003) 657 e 660.
[111] C. Flexner, HIV drug development: the next 25 years, Nat. Rev. Drug Disc. 6 (2007) 959 e 966.
[112] A.O.A. Allah, Synthesis and biological studies of some benzopyrano[2,3-c] pyrazole derivatives, Il Farm. 55 (2000) 641 e 649.
[113] M.I. Johson, D.F. Horth, Present status and future prospects for HIV therapies, Science 260 (1993) 1286 e 1293.
[114] S.R. Nagarajan, G.A.D. Crescenzo, D.P. Getman, H. Lu, J.A. Sikorski, J.L. Walker, J.J. McDonald, K.A. Houseman, G.P. Kocan, N. Kishore, P.P. Mehta, C.L. Funkes-Shippya, L. Blystonea, Discovery of novel benzothiazolesulfonamides as