Acylation of 3-hydrazino-5,6-diphenyl-1,2,4-triazine (2) and hydrazine hydrate (7) with 4-aryl-1,3,7-triphenyl-8-oxa-1,2,6-triazaspiro[4.4]nona-2,6-dien-9-ones 5a,b gave the corresponding heterocyclic carbohydrazides 6a,b and 8a,b respectively. Conversion of compounds 8a,b into the versatile carbohydrazide derivatives 9a-g, 10, 13 and the related oxadiazoles 11, 12a,b was undertaken. A primary in vitro test of compound 8a (concentration 10-4 M) showed activity against leukemia cell lines (CCRF-CEM, K-256, MOLT-4, PRMI-8226, SR).
Selective synthesis and reactions of different 6-substituted-2-beta-D-galactosyl-3-thioxo-2,3-dihydro-1,2,4-triazin-5(4H)-ones using the developed amino or aryl protecting group strategy were investigated. Primary human anticancer screening of twelve selected compounds (in vitro) resulted in an active compound against both MCF7 (Breast) and SF-268(CNS) cell lines.
4‐Amino‐3‐(methylthio)‐6‐R‐1,2,4‐triazin‐5(4H)‐ones 6 – 10 react with anthranilic acid to yield the 1‐amino‐3‐R‐2H‐as‐triazino[3,2‐b]quinazoline‐2,6(1H)‐diones 17 – 21 rather than the expected as‐triazino[3,4‐b][1,3,4]benzotriazepines 12 – 16. Compounds 17 – 21 were deaminated into compounds 22 – 26. Heating of the N‐benzylidene derivatives of 6 – 10 (27 – 31) with anthranilic acid also led to the formation of 22 – 26 with extrusion of benzonitrile.
(Table 1). This structure assignment is based on spectroscopic evidence mainly uv, 13C-nmr and 'H-nmr. Thus comparing the uv-spectra of the Sethyl derivative 9). the N-methyl derivative 1Oc and the glucosyl derivative 7b, we found that 9 and 7b had different absorption maxima (one maximum at 284 nm for 9 and two maxima at 312 and 318 nm for 7b). On the other hand, 1Ochad an absorption maximum at 320 nm similar to that of 7b (3 18 nm). 1Oc was prepared by first methylating 10a") in methanolic NaOCH3 with H3CI to give 10b followed by thiation of the latter with Lawesson's reagent. The chemical shifts of the C-atoms of the heterocyclic moiety together with that of the anomeric C-atom are in agreement with the N-glucoside structure rather than the Sglucoside isomer"). This, together with the appearance of the anomeric H-signal in the 'H-nmr spectrum of 7a at 6.80 ppm, with J = 9 Hz, similar to the values reported for N-glucosyl derivative^^^'), gives additional support that glucosidation took place selectively at N-1 of the triazine ring and excludes S-glucosidation. This also suggests that the anomeric H acquires an axial conformation and consequently the glucosidic linkage has b-configuration. This reveals a S~2 -m action between 1 and the triazines 6ad with inversion at the anomeric C. This is not surprising since the acetoxy group in position 2 of 1 is in a cisconfiguration with respect to the
Glucosidation of the new 8-amino-6-benzyl(or substituted benzyl)-2,8-dihydro-1,2,4-triazolo[4,3-b][1,2,4]triazin-7(3H)-ones (3a-d) with 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide 4 gave the corresponding N-glucosides 5a-d. Chemical transformations leading to new functionalities have also been achieved to give compounds 7-12. Antimicrobial activity of compounds 5a-c against Aspergillus fumigatus, Penicillium italicum, Syncephalastrum racemosum, Candida albicans, Staphylococcus aureus, Pseudomonas aeruginosa, Bacillus subtilis, Escherichia coli is described.
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