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A series of newly disubstituted (compounds 4a,b) and trisubstituted 1,3,4-thiadiazines 5a-l with various substituents was prepared utilizing different thiosemicarbazides and 3-α-bromoacetylcoumarins as starting compounds. The structures of the synthesized 1,3,4-thiadiazines are elucidated and confirmed utilizing the corresponding analytical and spectroscopic data. All of the new thiadiazine derivatives were tested for their antioxidant activity, employing different antioxidant assays (DPPH scavenging activity, iron chelating activity, power reducing activity). Compounds 5b, 5f, 5j and 4b were proven to be the best DPPH radical scavengers, while compounds 5h and 5j have shown the best iron chelating activity. Thiadiazine derivatives were also tested on their antifungal activity against four mycotoxicogenic fungi, Aspergillus flavus, A. ochraceus, Fusarium graminearum and F. verticillioides. The best antifungal against A. flavus was proven to be compound 5e, while compounds 4a and 5c were the best antifungals on A. ochraceus, and compound 5g showed the best antifungal activity on F. verticillioides.

New triazolothiadiazine derivatives were synthesized via the ring closure reaction of 4-amino-5-substituted-2,4-dihydro-3H-1,2,4-triazol-3-thiones with phenacyl bromides. The compounds were tested in vitro against various Candida species and compared with ketoconazole. Among these compounds, the compound bearing cyclohexyl moiety and p-chlorophenyl substituent on triazolothiadiazine ring (2i) was found to be the most potent derivative against Candida albicans (ATCC 90028). It is clear that there is a positive correlation between anticandidal activity and two functional moieties, namely cycloaliphatic group and p-chlorophenyl substituent on triazolothiadiazine ring. The compounds were also investigated for their cytotoxic effects using MTT assay. Compound 2a exhibited the highest cytotoxic activity, whereas compound 2f possessed the lowest cytotoxic activity against NIH/3T3 cells., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Some new 5-methoxy/ethoxy-2,3-[2'-(3''-chloro-2''-oxo-4''-substituted-aryl-1''-azetidinyl)-1',3',4'-thiadiazino]indoles 13-20 and 5-methoxy/ethoxy-2,3-[2'-(2''-substituted-aryl-4''-oxo-1'',3''-thiazolidin-3''-yl)-1',3',4'-thiadiazino]indoles 21-28 have been synthesized from 5-methoxy/ethoxy-2,3-[2'-(substituted-benzylidinylimino)-1',3',4'-thiadiazino]indoles 5-12. These newly synthesized compounds were characterized by elemental and spectral analysis. Further, compounds 5-28 of the present series have been screened for their antibacterial and antifungal activities. Both minimal inhibitory concentration (MIC) and inhibition zones were determined in order to monitor the efficacy of the synthesized compounds. Compounds 14 and 16 were found to be the most potent members of the present series, they showed maximal antibacterial and antifungal properties much better than the standard drugs.

The purpose of this study is based upon design and synthesis of a new series of flexible molecules of 3,4,5,6-tetrahydro-2H-1,3,5-thiadiazine-2-thione (THTT) derivatives depending upon incorporation of 2-aminoethanol as a part of the polar moiety in this nucleus. Thirteen derivatives of 3-substituted-5-(2-hydroxyethyl)-3,4,5,6-tetrahydro-2H-1,3,5-thiadiazine-2-thione were synthesized by reaction of the appropriate alkyl, cycloalkyl, aralkyl amine, or glycine with carbon disulphide, formaldehyde, and 2-aminoethanol. The structures of the target compounds were elucidated using spectral methods as well as elemental analyses. A mass-spectrometry study was carried out on representatives of the synthesized derivatives. The title compounds were tested for their antibacterial activity in vitro against some gram positive and gram negative bacteria. The in-vitro antifungal activity was tested against dermatophytic, saprophytic, phytopathogenic, and antagonistic fungi. In most cases, the newly synthesized compounds 4-16 exhibited a considerable inhibitory effect on the growth of some of the tested organisms in comparison to that of ampicillin or muconazole as reference drugs. Moreover, the results indicated that the polar hydroxyethyl group at the N5- and the lipophilic one at the N3-positions are essential for the antimicrobial activity of the tested compounds.

Thirty one new 6-aryl-3-{(4-substituted phenoxy) methyl}-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles (6a-s) and 6-aryl-3-[(4-substituted phenoxy methyl]-7H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines (7a-l) have been synthesized from 4-thioalkyl phenols (1a-b) through a multi-step reaction sequence. Compounds 1a-b reacted with ethyl chloroacetate in presence of acetone and potassium carbonate to give ethyl [4-(thioalkyl) phenoxy] acetates (2a-b). Further, 2a was oxidized to [4-(methyl sulphonyl) phenoxy] acetate (2c) using hydrogen peroxide in acetic acid. Reactions of (2a-c) with hydrazine hydrate in alcoholic medium furnished 2-[4-thiosubstituted phenoxy] acetohydrazides (3a-b) and 2-[4-methyl sulphonyl phenoxy] acetohydrazide (3c) which on treatment with carbon disulphide and methanolic potassium hydroxide yielded corresponding potassium dithiocarbazates (4a-c). They were then converted to 4-amino-5-[(4-thioalkyl phenoxy) methyl]-4H-1,2,4-triazole-3-thiols (5a-b) and 4-amino-5-[(4-methyl sulphonyl phenoxy) methyl]-4H-1,2,4-triazole-3-thiol (5c) by refluxing them with aqueous hydrazine hydrate. The title compounds 6a-s were prepared by condensing 5a-c with various aromatic carboxylic acids in presence of phosphorus oxychloride. The intermediates 5a-c, on condensation with various substituted phenacyl bromides afforded a series of title compounds (7a-l). The structures of new compounds 2a-7l were established on the basis of their elemental analysis, IR, (1)H NMR, (13)C NMR and mass spectral data. All the title compounds were subjected to in vitro antibacterial testing against four pathogenic strains and antifungal screening against three fungi. Preliminary results indicate that some of them exhibited promising activities and they deserve more consideration as potential antimicrobials.

In a search for promising antibacterial and antifungal compounds, two new series of 2, 3-bis(5-alkyl-2-thiono-1, 3, 5-thiadiazin-3-yl)propionic acid 1 and their corresponding N, N-dimethylpropionamide 6 have been synthesized. The reaction of 2, 3-diaminopropionate 3, carbon disulfide, formaldehyde, and the appropriate alkyl amines furnished the title compound 1. N, N-dimethylpropionamides 6 were obtained by the reaction of 1 with dimethyl amine in the presence of POCl(3). The newly prepared compounds were screened in vitro against certain strains of Gram-positive and Gram-negative bacteria and compared with nalidixic acid and ciprofloxacin. Moreover, the title compounds were tested for their antifungal activity in vitro against Candida albicans, phytopathogenic, Penicillum expansum and Trichoderma hazianum, and aflatoxin-producing Aspergillus flavus. These compounds exhibit varied activity against the tested pathogenic bacteria and remarkable inhibitory effects on growth or sporulation of some of the tested fungal species.

The new title derivatives (4b-h and 5a-i) were synthesized by reaction of the appropriate primary amine, carbon disulphide, and formaldehyde. These derivatives were prepared in order to study the effects of introducing polar groups at N3 or N5 or at both positions on the biological activity. The compounds were tested for their antifungal activity in vitro against pathogenic (Trichophyton rubrum and Candida albicans), phytopathogenic (Penicillum expansum, Trichoderma hazianum, and Fasarium oxysporum), and aflatoxin-producing (Aspergillus flavus) fungi. These compounds exhibited varied inhibitory effects on growth or sporulation of some tested fungal species.

In a search for promising antifungal compounds, nine new 3,3'-ethylenebis(5-alkyl-1,3,5-thiadiazine-2-thiones) were synthesized by the reaction of ethylene diamine, carbon disulfide, formaldehyde, and the appropriate alkyl amine. The title compounds were tested for their antifungal activity in vitro against pathogenic (Trichophyton rubrum and Candida albicans), phytopathogenic (Penicillum expansum, Trichoderma hazianum, and Fasarium oxysporum), and aflatoxin producing (Aspergillus flavus) fungi. These compounds exhibited varied inhibitory effects on growth or sporulation of some tested fungal species.

Title compounds (5) were conveniently prepared from 5-aryl-3-mercapto-1,2,4-triazoles (1) and chloro-sulphonyl isocyanate (CSI) to give 8-aryl-4-(5H)-oxo-1,2,4-triazolo-[4,3-b]-1,4,2,6-dithiadiazine -6,6-dioxide (2). The Compound (2) and one suspension of 2-(benzyloxycarbonylamino) akanoic acid (3) in the presence of BOP reagent afforded Z-derivatives 8-aryl-5-(2-benzyloxycarbamoyl)alkanoyl-4(5H)-oxo- 1,2,4-triazolo[4,3-b]-1,4,2,6-dithiadiazine 6,6-dioxide (4). The Z-derivatives (4) gave aspected product (5) when treated with Pd-c 5% and formic acid in DMF. These compounds have been tested in vitro for their fungicidal activity against Aspergillus niger, Fusarium oxisporum and Cephalosporium saccharii and results were compared with their parent dithidiazines.

Ten new 3-(2-phenethyl)-5-substituted-tetrahydro-2H-1,3,5-thiadiazine-2- thiones were synthesized by the reaction of phenylethylamine with carbon disulfide and potassium hydroxide, followed by formaldehyde and appropriate amino acids. The structures of these compounds have been confirmed by UV, IR, 1H-NMR and elementary analysis. The antifungal activities of the compounds were tested by tube dilution method against yeast-like fungi (Candida albicans, C. parapsilosis, C. stellatoidea and C. pseudotropicalis) and minimal inhibitory concentration (MIC) and minimal fungicidal concentration (MFC) values were determined. All compounds proved to be highly effective against yeast-like fungi (MFC range: 1.56-12.5 micrograms/ml).

A number of new 3-benzyl-5-[alpha-(substituted)carboxymethyl]- tetrahydro-2H-1,3,5-thiadiazine-2-thiones has been synthesized as prodrugs by incorporating the amine group of some amino acids into tetrahydro-2-H-1,3,5-thiadiazine-2-thione ring. The compounds have been prepared by the reactions of benzylamine with potassium hydroxide, carbon disulphide formaldehyde and various amino acids. The structures of the compounds have been elucidated by UV, IR, 1H-NMR, mass spectra and elementary analysis. The in vitro activity of these compounds against yeast-like fungi (Candida albicans, C. parapsilosis, C. pseudotropicalis, C. stellatoidea) was investigated by tube dilution method. Their minimal inhibitory concentration (MIC) and minimal fungicidal concentration (MFC) values were determined. All the compounds were found to be active between 3.12-12.5 micrograms/ml against the four fungi tested.

Starting from 3-aryl-4-amino-5-mercapto-4H-1,2,4-triazoles (II), two series of 3,6-disubstituted 7H-1,2,4-triazol [3,4-b] [1,3,4] thiadiazines (III) and their 5-carboxymethylthio derivatives (IV) were prepared. From the mercapto-amino-triazoles (II) because of their reactivity in some oxidising media, were obtained the triazole derivatives (V), (VI) and (VII). The synthesis of the alpha-thioketones (VIII) of 3-aryl-5-mercapto-1,3,4-oxadiazoles (I), used in alternative synthesis of triazole-thiadiazines (III), is also reported. All the substances described were subjected to biological screening. In the tests, the carboxymethylthiotriazole (IV) showed weak antiinflammatory activity (carrageenin edema) and more consistent scavanger activity, in vitro, on superoxide anions. The triazole-thiadiazines (III) and triazoles (II), (V) and (VI) showed moderate antimycotic activity.