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Abstract When 10H-phenothiazine (1) was treated with ethyl chloroacetate in acetone and in the presence of anhydrous K2CO3, the corresponding 10- (carbethoxymethyl)-10H-phenothiazine (69) was obtained in 84 % yield (Scheme 1). solution of 69 in DMF was treated with o-phenylenediamine under reflux to afford 70 in 69 % yield (Scheme 2). mixture of 69, hydrazine hydrate, and methanol was heated under reflux to yield white needles of 71 in 87 % yield (Scheme 3). The hydrazide 71 was added to ammonium thiocyanate in dry benzene and the mixture was heated under reflux to afford 72 in 83 % yield (Scheme 4). Treatment of 72 with 1N-KOH solution in ethanol under reflux followed by acidification with conc. HCl gave crystalline fibers of the thiol derivative 73 in 78 % yield (Scheme 5). The hydrazide 71 was treated with phenyl isothiocyanate in abs. ethanol to afford a white solid of 74 in 90 % yield (Scheme 6). A mixture of compound 74 and 10% sodium hydroxide solution was refluxed then, acidified with acetic acid to pH 5 to yield 75 in 74 % yield (Scheme 7). Sodium salt of 70 was treated with 1-chloro-2-methoxyethane under refluxed to give a brown ppt. of 76 in 72 % yield (Scheme 8). A sodium salt of 70 was alkylated with 2-(2-chloroethoxy)ethanol under reflux to give a black ppt. of 77 in 77 % yield (Scheme 9). Sodium salt of 73 was reacted with 1-chloro2-methoxyethane to give a brown ppt. of 78 in 72 % yield (Scheme 10). Alkylation of the sodium salt of 73 with 2-(2-chloroethoxy)ethanol afforded 79 in 77 % yield (Scheme 11). Alkylation of 75 with 1-chloro2-methoxyethane gave 80 in 75 % yield (Scheme 12). Treatment of the sodium salt of 75 with 2-(2-chloroethoxy)ethanol afforded the product 81 in 79 % yield (Scheme 13). The hydrazide derivative 71 was condensed with the appropriate monosaccharide [D-(+)-Xylose, D-(+)-Glucose, D-(+)-Galactose] in the presence of a catalytic amount of glacial acetic acid to afford the corresponding sugar hydrazones 82-84 in 75-83% yields (Scheme 14). The O-acetyl sugar hydrazones 85-87 were prepared in 92-97% yields by treating of the sugar hydrazones 82-84 with acetic anhydride in pyridine at room temperature (Scheme 15). The oxadiazoline derivatives 88-90 were prepared in 73-78% yields by treating of the sugar hydrazones 82-84 with acetic anhydride at boiling temperature (Scheme 16). Treatment of 75 with hydrazine hydrate in ethanol under reflux afforded 91 in 95% yield (Scheme 17). Treatment of the potassium salt of 91 with carbon disulphide under reflux followed by acidification with dilute hydrochloric acid gave 92 as a white powder in 79 % yield (Scheme 18). Triazolo tetrazole derivative 93 was synthesized in 80% yield by treating of 91 with sodium nitrite solution in 50% aqueous HCl (Scheme 19). Acetyl acetone and/or diethylmalonate were added to a solution of 91 in dioxane as well as a few drops of triethylamine (TEA). The mixture was refluxed to afford 94 and 95 in 82% and 84% yields, respectively (Scheme 20 & 21). The synthesized compounds were screened in vitro for their antimicrobial activities against Gram –ve and Gram +ve bacteria), as well as some Fungi. The antimicrobial activity results and structure activity relationship indicated that the attachment of acyclic sugar moieties, triazole, tetrazole, and thiagiazole ring system and/or phenothiazine resulted in increase of antimicrobial activity. All compounds possess the highly significant effect against breast cancer cell line (MCF7) and this is might be due to the presence of such NH-C=O and NHC=S moieties in addition to phenothiazine moiety. The results of the viral screening against HBV of some selected compounds indicated that deprotected derivatives showed moderate viral replication inhibition and mild cytotoxicity with selective indecies 166.6 ~ 500.0. On the other hand, theprotected derivatives showed low inhibition and high cytotoxicity with selective indecies 20.0 ~ 76.9. |