Abstract
N-alkylation of azaphenothiazines using dibromoalkanes or dibromoalkenes did not result in the formation of bis-azaphenothiazines under known conditions such as refluxing, for more than 100 h, with NaNH2/xylene or NaH/toluene. However, when the same reaction was tried with NaH/DMF at −5 °C to r.t., it yielded the desired product in 68–71 % yield. These novel bis-azaphenothiazines containing a suitable alkyl or alkenyl spacer were found to possess moderate to significant antimicrobial activities against three gram positive bacteria (Staphylococcus aureus, Bacillus subtilis, and Staphylococcus epidermis), four gram negative bacteria (Escherichia coli, Pseudomonas aeruginosa, Salmonella typhi, and Klebsiella pneumoniae) as well as four fungi (Aspergillus niger, Aspergillus fumigatus, Aspergillus flavus, and Candida albicans). Compounds 2b–d were found to exhibit strong antifungal activity, comparable to the standard drug miconazole against A. niger and A. fumigatus.
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References
Atkinson ER, Russ PL, Tucker MA, Rosenberg FJ (1971) Neuropharmacological profile of 1-azaphenothiazine-10-thiolcarboxylate. J Med Chem 14(10):1005–1007
Beschke H, Schuler W (Deutsche Gold- und Silber- Scheideanstalt Vorm. Roessler) (1964) 1-Azaphenothiazine derivatives as antihypertensive agents. 3 pp DE 1166206 19640326 Chem. Abstr. 60:90907
Brana MF, Castellano JM, Perron D, Maher C, Conlon D, Bosquet PF, George J, Qian XD, Robinson SP (1997) Chromophore-modified bis-naphthalimides: synthesis and antitumor activity of bis-dibenz[de, h]isoquinoline-1,3-diones. J Med Chem 40(4):449–454
Chaires JB, Leng FF, Przewloka T, Fokt I, Ling YH, Perez-soler R, Priebe W (1997) Structure-based design of a new bisintercalating anthracycline antibiotic. J Med Chem 40(3):261–266
Chuickshank R, Dugid JP, Marmon DP, Swain RHA (1975) In medicinal microbiology vol 2. Churchill-livingstone, Edinburg
Clarke FH, US Patent (1965) Antidepressant 10-[3-(dimethylamino)propyl]-3-azapheno-thiazine. US 3196076. Chem. Abstr. 63:453917
Giuliano H, Sakate M, Ramos AO (1965) Ganglion block produced by selvigon. Revista da Fauldade de Farmaciae Bioquimica da Universidade de Sao Paulo 3(2):241–247
Gloria TS (1968) Chemical-pharmacologgical study of 1-azaphenothiazine derivatives. Revista da Fauldade de Farmaciae Bioquimica da Universidade de Sao Paulo 6(1):63–113
Gupta A, Sakhuja R, Jain SC (2007) Microwave-assisted synthesis of 10-(phthalimidoalkyl)-halosubstitutedpyrido[3,2-b][1,4]-benzothiazine in dry media. Synth Commun 37(22):4059–4069
Hernandez L, Cholody WM, Hudson EA, Resau JH, Pauly G, Michejda CJ (1995) Mechanism of action of bisimidazoacridones, new drugs with potent, selective activity against colon cancer. Cancer Res 55:2338–2345
Krystian P, Malgorzata J, Beata MM, Michal Z, Jolanta A, Maja K (2010) Anticancer activity of newly synthesized azaphenothiazines from NCI’s anticancer screening bank. Pharmacol Rep 62(2):319–332
Ledochowski Z, Bogucka M, Cybulska B, Wysocka SB (1963) 10-(3-Dimethylaminopropyl)-1-azaphenothiazine hydrochloride. Przem Chem 42(8):427
Lenke D, Neteler B, Brock N (1971) Pharmacological activity of new phenothiazine and azaphenothiazine derivatives. Arzneimittel Forschong 21(2):288–293
May BC, Fafarman AT, Hong SB, Rogers M, Deady LW, Prusiner SB, Cohen FE (2003) Potent inhibition of scrapie prion replication in cultured cells by bis-acridines. Proc Natl Acad Sci USA 100(6):3416–3421
Nitiss JL, Zhou J, Rose A, Hsiung Y, Gale KC, Osheroff N (1998) The bis(naphthalimide) DMP-840 causes cytotoxicity by its action against eukaryotic topoisomerase. Biochemistry 37(9):3078–3085
Swati Shukla S, Mishra AK, Prakash L (1996) Synthesis of some novel 1-azaphenothiazines and their mesoionics as analogs of potent CNS-depressants. Phosphorus Sulfur Silicon Relat Elem 117(1):111–120
Vennerstrom JL, Ager AL Jr, Dorn A, Andersen SL, Gerena L, Ridley RG, Milhous WK (1998) Bisquinolines. 2. Antimalarial N,N-bis(7-chloroquinolin-4-yl)heteroalkanediamines. J Med Chem 41(22):4360–4364
Yale HL, Sowinski F (1958) 10-(Dialkylaminoalkyl)-pyrido[3,2-b][1,4]benzothiazine (1-azaphenothiazine) and related compounds. J Am Chem Soc 80:1651–1652
Yang JF, Cao H, Liu H, Li BQ, Ma YM (2011) Synthesis and bioactivity of novel bis-heterocyclic compounds containing pyrazole and oxadiazoline. J Chin Chem Soc 58(3):369–375
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Author (K.K) and (R.S) are thankful to CSIR (Council of Scientific and Industrial Research), New Delhi for research fellowship; and to Dr. Siva S Panda and Mahesh Chand for biological evaluation.
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Kushwaha, K., Sakhuja, R. & Jain, S.C. Synthesis and antimicrobial activity of novel bis-azaphenothiazines. Med Chem Res 22, 4459–4467 (2013). https://doi.org/10.1007/s00044-012-0454-7
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DOI: https://doi.org/10.1007/s00044-012-0454-7