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Matrix metalloproteinases (MMPs) are key signaling modulators in the tumor microenvironment. Among MMPs, MMP-2 and MMP-9 are receiving renewed interest as validated druggable targets for halting different tumor progression events. Over the last decades, a diverse range of MMP-2/9 inhibitors has been identified starting from the early hydroxamic acid-based peptidomimetics to the next generation non-hydroxamates. Herein, focused 1,2,4-triazole-1,2,3-triazole molecular hybrids with varying lengths and decorations, mimicking the thematic features of non-hydroxamate inhibitors, were designed and synthesized using efficient protocols and were alkylated with pharmacophoric amines to develop new Mannich bases. After full spectroscopic characterization the newly synthesized triazoles tethering Mannich bases were subjected to safety assessment via MTT assay against normal human fibroblasts, then evaluated for their potential anticancer activities against colon (Caco-2) and breast (MDA-MB 231) cancers. The relatively lengthy bis-Mannich bases 15 and 16 were safer and more potent than 5-fluorouracil with sub-micromolar IC50 and promising selectivity to the screened cancer cell lines rather than normal cells. Both compounds upregulated p53 (2–5.6-fold) and suppressed cyclin D expression (0.8–0.2-fold) in the studied cancers, and thus, induced apoptosis. 15 was superior to 16 in terms of cytotoxic activities, p53 induction, and cyclin D suppression. Mechanistically, both were efficient MMP-2/9 inhibitors with comparable potencies to the reference prototype hydroxamate-based MMP inhibitor NNGH at their anticancer IC50 concentrations. 15 (IC50 = 0.143 µM) was 4-fold more potent than NNGH against MMP-9 with promising selectivity (3.27-fold) over MMP-2, whereas 16 was comparable to NNGH. Concerning MMP-2, 16 (IC50 = 0.376 µM) was 1.2-fold more active than 15. Docking simulations predicted their possible binding modes and highlighted the possible structural determinants of MMP-2/9 inhibitory activities. Computational prediction of their physicochemical properties, ADMET, and drug-likeness metrics revealed acceptable drug-like criteria.

Tuberculosis (TB) caused by Mycobacterium tuberculosis is still a serious public health concern around the world. More treatment strategies or more specific molecular targets have been sought by researchers. One of the most important targets is M. tuberculosis’ enoyl-acyl carrier protein reductase InhA which is considered a promising, well-studied target for anti-tuberculosis medication development. Our team has made it a goal to find new lead structures that could be useful in the creation of new antitubercular drugs. In this study, a new class of 1,2,3- and 1,2,4-triazole hybrid compounds was prepared. Click synthesis was used to afford 1,2,3-triazoles scaffold linked to 1,2,4-triazole by fixable mercaptomethylene linker. The new prepared compounds have been characterized by different spectroscopic tools. The designed compounds were tested in vitro against the InhA enzyme. At 10 nM, the inhibitors 5b, 5c, 7c, 7d, 7e, and 7f successfully and totally (100%) inhibited the InhA enzyme. The IC50 values were calculated using different concentrations. With IC50 values of 0.074 and 0.13 nM, 7c and 7e were the most promising InhA inhibitors. Furthermore, a molecular docking investigation was carried out to support antitubercular activity as well as to analyze the binding manner of the screened compounds with the target InhA enzyme’s binding site.

Objective: 5-Amino-2-alkyl/glycosylthio-1,3,4-thiadiazoles have been synthesized by the reaction of 5-amino-1,3,4-thiadiazole-2-thiol with a variety of alkylating agents or glycosyl halides in the presence of anhydrous potassium carbonate in dry acetone. Methods: The structures of the newly synthesized compounds have been established based on their spectral data (FT-IR, 1H- and 13C-NMR) and mass spectrometry. They were tested for their antioxidant behaviour by the use of 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging method. The in silico pharmacokinetics ADME properties of the potent antioxidant compounds were investigated by using Accelrys Discovery Studio (DS) 2.5 software. Results and Conclusion: Regioselective alkylation and glycosylation of 5-amino-1,3,4-thiadiazole-2-thiol were noticed during its reaction with alkylating agents and glycosyl halides. Alkylating agents gave the Sfunctionalized derivatives, while the acetylated glycosyl halides afforded the S-glycosylated products together with their respective N-acetyl derivatives. The benzoylated glycosyl halide behaved in a different manner and gave N-glycoside analogue of 1,3,4-thiadiazole-2(3H)-thione, in addition to the expected sulfanyl S-glycoside. Most of the synthesized compounds showed noticeable antioxidant activity with respect to ceftriaxone as a standard drug. Some of the most active compounds showed acceptable predicted pharmacokinetics and druglikeness properties.

Ethyl (benzimidazol-1-yl)acetate was subjected to hydrazinolysis with hydrazine hydrate to give (benzimidazol-1-yl)acetohydrazide. The latter was reacted with various aromatic aldehydes to give the respective arylidene (1H-benzimidazol-1-yl)acetohydrazones. Solutions of the prepared hydrazones were found to contain two geometric isomers. Similarly (2-methyl-benzimidazol-1-yl)acetohydrazide was reacted with various aldehydes to give the corresponding hydrazones. The antibacterial activity was evaluated in vitro by minimum inhibitory concentration (MIC) against Agrobacterium tumefaciens (A. tumefaciens), Erwinia carotovora (E. carotovora), Corynebacterium fascians (C. fascians) and Pseudomonas solanacearum (P. solanacearum). MIC result demonstrated that salicylaldehyde(1H-benzimidazol-1-yl)acetohydrazone (4) was the most active compound (MIC = 20, 35, 25 and 30 mg/L against A. tumefaciens, C. fascians, E. carotovora and P. solanacearum, respectively). Quantitative structure activity relationship (QSAR) investigation using Hansch analysis was applied to find out the correlation between antibacterial activity and physicochemical properties. Various physicochemical descriptors and experimentally determined MIC values for different microorganisms were used as independent and dependent variables, respectively. pMICs of the compounds exhibited good correlation (r = 0.983, 0.914, 0.960 and 0.958 for A. tumefaciens, C. fascians, E. carotovora and P. solanacearum, respectively) with the prediction made by the model. QSAR study revealed that the hydrophobic parameter (ClogP), the aqueous solubility (LogS), calculated molar refractivity, topological polar surface area and hydrogen bond acceptor were found to have overall significant correlation with antibacterial activity. The statistical results of training set, correlation coefficient (r and r 2), the ratio between regression and residual variances (f, Fisher’s statistic), the standard error of estimates and significant (s) gave reliability to the prediction of molecules with activity using QSAR models. However, QSAR equations derived for the MIC values against the tested bacteria showed negative contribution of molecular mass.

The N-(β-hydroxyethyl)acetamidine ( 4 ) was prepared. Mesylation of 8 gave the 1,3-di- O -benzyl-2- O -methanesulfonylglycerol ( 9 ). Nucleophilic displacement of the mesyloxy group in 9 with ethanolamine and morpholine gave 11 and 12 , respectively. Their catalytic hydrogenation gave 2-deoxy-2-(1-hydroxyeth-2-yl)amino-glycerol ( 5 ) and 2-deoxy-2-(morpholin-4-yl)glycerol ( 13 ). The inhibition of the β-D-glucosidase enzyme from sweet almond by 4, 5 and 13–16 has been studied.

Bull. Chem. Soc. Ethiop., 3(2), 97-102 (1989).

The N-(β-hydroxyethyl)acetamidine ( 4 ) was prepared. Mesylation of 8 gave the 1,3-di- O -benzyl-2- O -methanesulfonylglycerol ( 9 ). Nucleophilic displacement of the mesyloxy group in 9 with ethanolamine and morpholine gave 11 and 12 , respectively. Their catalytic hydrogenation gave 2-deoxy-2-(1-hydroxyeth-2-yl)amino-glycerol ( 5 ) and 2-deoxy-2-(morpholin-4-yl)glycerol ( 13 ). The inhibition of the β-D-glucosidase enzyme from sweet almond by 4, 5 and 13–16 has been studied.

Publisher Summary The Dimroth rearrangement (DR) is a translocation of two heteroatoms in a heterocyclic system, with or without changing its ring structure. The conversion of a heterocycle to a rearranged isomeric product can give one or two isomers via anintermediate, which selectively or specifically forms one of them as the major one. The stability of the rearranged product is the driving force for its formation, which may lead to the preference of one isomer. The heteroatoms which exchange positions in the rearrangement are S, N, O, and Se. DR can be divided into two types based on the positions of the translocating heteroatom(s): either both in the ring or one in the ring and the other located in an exocyclic position of that ring. This chapter discusses the translocation of heteroatoms between rings in fused heterocycles, and the translocation of exo-and endo-heteroatoms within a heterocyclic ring. In the process of rearrangement by translocation of heteroatoms between rings in fused heterocycles, the translocated heteroatoms are part of the ring. The translocation process changes the position of the heteroatom or the substituent on that ring leading to either a retained or a changed ring structure. The presence of a heteroatom within a five-membered ring and also at an exocyclic position of the adjacent ring is a promoting factor for the rearrangement. In the translocation of exo-and endocyclic heteroatoms in heterocyclic rings the translocation of heteroatom X (endocyclic in the ring) and Y (exocyclic to the ring) takes place during the rearrangement. All the processes are driven by the stability of the product, solvent, aromaticity of the ring, heteroatom valence, and bulkiness of the substituent.

The reaction of hydrogen bromide in acetic acid with a number of l -threo-glycerolylpyrazolinediones and their partially acetalated, acetylated, benzoylated, and p-toluenesulfonylated derivatives has been investigated. The presence of an O-isopropylidene ring at the C-1 and C-2 positions and/or an acetyl group at position C-3 does not affect the mode of the reaction. The products are 1,3-dibromo-1,3-dideoxy-2-O-acetyl- l -erythro-glycerolyl derivatives, which are identical with those obtained from the corresponding triol precursor. The conditions of the reaction promote ester migration via the apparent formation of a dioxolanylium ion. However, ester migration was not observed in the corresponding 3-benzoate and 3-(p-toluenesulfonate), whereby 1-bromo-1-deoxy derivatives having the l -erythro configuration were obtained. The reaction of 6-bromo-6-deoxy-dehydro- l -ascorbic acid with phenylhydrazine gave a mixture of the corresponding bis(phenylhydrazone) and the 3-bromo-3-deoxy glycerolyl derivative of the pyrazolinedione.

Publisher Summary This chapter explores that dimedone is a versatile precursor for annulated heterocycles. Dimedone(1) is an alicyclic compound having 1,3-dicarbonyl groups flanked by a methylene group and exists in a tautomeric transenolized form where intramolecular hydrogen bonding is not possible. Dimedone is an excellent precursor for partially hydrogenated fused heterocycles where two of the carbon atoms of dimedone are part of the backbone of the formed heterocycles. The chapter illustrates that dimedone's structural features and its reactivity to form more functionalized derivatives have led to the construction of a wide range of fused or spiral biheterocycles. Finally, this chapter emphasizes the role of 1 in the synthesis of fused heterocycles, classified according to the size of the ring and the number of heteroatoms in the heterocycle fused to the cyclohexane ring and subdivided according to the heteroatoms and their arrangement in the ring.

The synthesis of the (2,4-dichlorophenoxy)acetylhydrazones of a number of monosaccharides is described. The reaction of the corresponding d -galactose derivative with acetic anhydride in pyridine was investigated. Penta- O -acetyl- aldehydo - d -galactose (2,4-dichlorophenoxy)acetylhydrazone was prepared by reaction of the hydrazine with penta- O -acetyl- aldehydo - d -galactose, and its 1 H-n.m.r. spectrum indicated its existence as two geometric isomers. Reaction of the pentaacetate with boiling acetic anhydride caused its acetylative heterocyclization into 3-acetyl-5-[(2,4- dichlorophenoxy)methylene]-2-(1,2,3,4,5-penta- O -acetyl- d - galacto -pentitol-1-yl)- 1,3,4-oxadiazoline. A generalized mechanism for the heterocyclization, based on “soft” and “hard” acids and bases, is discussed. d - arabino -Hexos-2-ulose 2-(2,4- dichlorophenoxy)acetylhydrazone 1-phenylhydrazone was also prepared.

l -hreo-2,3-hexodiulosono-1,4-lactone 2-(p-methoxyphenylhydrazone) (1) was condensed with arylhydrazines to give mixed bishydrazones, whose acetylation gave the corresponding di-O-acetyl derivatives. The hydrazone 1 undergoes elimination of one molecule of water per molecule during, the acetylation, and gives 4-(2-acetoxy- ethylidene)-4-hydroxy-2,3-dioxobutano-1,4-lactone 2-(p-methoxyphenylhydrazone), which reacts with methylhydrazine, via a ring transformation process, to give 1-methyl-3-(L-methylpyrazolin-3-yl)-4,5-pyrazoledione 4-(p-methoxyphenylhydrazone). Alkali rearranged the mixed bishydrazones to 1-aryl-3-( l -threo-glycerol-1-yl)-4,5- pyrazoledione 4-(p-methoxyphenylhydrazones), which gave triacetyl and tribenzoyl derivatives, and, upon periodate oxidation, afforded 1-aryl-3-formyl-4,5- pyrazolediones 4-(p-methoxyphenylhydrazones) that gave the corresponding phenylhydrazones. The n.m.r. and mass spectra of some of these derivatives have been investigated.

Precursors for the cyclic carboxyl equivalents of γ-aminobutyric acid (GABA) were synthesized. 5-O-(2, 3, 4, 6-Tetra-O-acetyl-β-D-gluco-pyranosyl-2-[4-phenyl-1, 2, 3-triazol-1-yl)methyl]-4H-pyran-4-one could be prepared by the glucosidation of 2-chloromethyl-5-hydroxy-4H-pyran-4-one. Nucleophilic displacement of the chlorine with azide ion gave the corresponding azidodeoxy derivative that upon 1, 3-dipolar cycloaddition with phenylacetylene yielded the triazolyl derivative.

The mode of action of arylhydrazines on kojic acid was investigated. Some novel types of compounds were isolated, and their structures were determined. The mechanism of the reactions is discussed.

3-[1-(p-Fluorophenylhydrazono)-L-threo-2,3,4-tri hydroxybutyl1-2-quinoxalinowe was prepared and trarrsformed to 3-[5-acetoxymetnyl-1-(p-fluorophenyl)-pyrazol-3-yl]-2-quinoxalinone. N-methylation, followed oy dehydrative cyclisation, gave the M-methyl-derivative of the latter pyrazole. Periodate oxidation gave a glyoxalyl derivative whose aldehyde functionality was confirmed by reduction and oximation.

l - threo -2,3-Hexodiulosono-1,4-lactone 2-(3-chlorophenylhydrazone) and 4- (2-acetoxyethylidene)-4-hydroxy-2,3-dioxobutano-1,4-lactone 2-(3-chlorophenylhydrazone) were prepared. The two geometric isomers of the corresponding bis(hydrazone) underwent an intramolecular rearrangement to 1-(3-chlorophenyl)- 3-( l - threo -glycerol-1-yl)-4,5-pyrazoledione 4-(3-chlorophenylhydrazone), which gave a tri- O -acetyl derivative upon acetylation and the anticipated formyl derivative upon periodate oxidation. Oxidation of the bis(hydrazone) with cupric chloride afforded the bicyclic compound 3,6-anhydro-3- C -(3-chlorophenylazo)- l - xylo -2-hexulosono-1,4-lactone 2-(3-chlorophenylhydrazone), whose acetylation afforded the mono- O -acetyl derivative.

The synthesis of some acyclic C-nucleoside analogs possessing thiadiazole rings was achieved by the heterocyclization of the 4-arylthiosemicarbazones of D-galactose, D-glucose, D-mannose, D-arabinose, and lactose, Acetylation of the thiadiazoles afforded the corresponding 2-(N-acetylarylamino)-5-polyacetoxyalkyl-1,3,4-thiadiazoles and periodate oxidation gave the corresponding 5-(arylamino)-1,3,4-thiadiazole-2-carbaldehyde.

Reaction of l -ascorbic acid with o -phenylenediamine and arylhydrazines afforded 3-(1-arylhydrazono- l - threo -2,3,4-trihydroxybutyl)-2-quinoxalinones ( 1–6 ). Whereas compounds 1–6 reacted with alkali to give 1-aryl-3-( l - threo -glycerol-1-yl)-flavazoles, the corresponding acetates ( 7 ) underwent deacetylation and rearrangement to 3-[1-aryl-5-(hydroxymethyl)pyrazol-3-yl]-2-quinoxalinones ( 20–24 ). Compounds 20–24 were also prepared from 1–5 by treatment with hot hydroxylamine hydrochloride. The action of boiling acetic anhydride on 1–5 or 7 afforded colorless products identified as the pyrazole acetates ( 15–19 ), which could also be obtained by the acetylation of compounds 20–24 . Deacetylation of 15 gave 20 . Oxidation of 20 with potassium permanganate gave the 5-carboxylic acid 26 . The i.r., n.m.r., and mass spectra of some of these compounds are discussed.

Various compounds related to the antibacterial, sulfanilamide drugs have been prepared from dehydro- l -ascorbic acid or its d -erythro analog by reaction with hydrazines related to sulfanilamide, sulfadiazine, sulfamerazine, sulfamethazine, and sulfamethoxydiazine, whereby the 2-mono- and 2,3-bis-(hydrazone) were isolated. After opening of the lactone ring in the bis(hydrazones) with alkali, nucleophilic attack, on the carbonyl group, of the imino nitrogen atom of the 3-hydrazone residue afforded 3-( l -threo-glycerol-1-yl)-1-phenyl- and -1-(p-sulfamylphenyl)-4,5-pyrazole-dione 4-(p-sulfamylphenlhydrazone) and the related 3-( d -erythro-glycerol-1-yl)compounds. Whereas acetylation of l -threo-2,3-hexodiulosono-1,4-lactone 2,3-bis(p-sulfamylphenylhydrazone) (9) and 3-( l -threo-glycerol-1-yl)-1-(p-sulfamylphenyl)-4,5-pyrazoledione 4-(p-sulfamylphenylhydrazone) (15) gave the O-acetyl derivatives, benzoylation of 15 gave the di-N-benzoy ltri-O-benzoyl compound. Reaction of 9 with cupric chloride gave 3,6-anhydro-3-(p-suIfamylphenylazo) - l -xylo-2-hexulosono-1,4-lactone 2-(p-sulfamylphenylhydrazone). The 3-( l -threo-glycerol-1-yl)-1-(p-sulfamylphenyl)flavazole (35) was prepared by the rearrangement of 3-[(1-p-sulfamylphenyl)hydrazono- l -threo-trihydroxybutyl]-2-quinoxalinont (33). Periodate oxidation of 15,33, and 35 gave 3-formyl-1-(p-sulfamylphenyl)-4,5-pyrazoledione 4-(p-sulfamylphenylhydrazone), 3-1-[(p-sulfamylphenyl)hydrazono]glyoxal-1-yl]-2-quinoxalinone, and 3-formyl-1-(p-sulfamylphenyl)flavazole, respectively. The i.r. and n.m.r. spectral data for some of these derivatives are reported.

Partial protection of the glycerolyl side-chain in 3-( L - threo -glycerol-1-yl)-1-phenyl-4,5-pyrazoledione 4-(phenylhydrazone) ( 2 ) was achieved via its acetonation; p -toluenesulfonylation then gave 3-(2,3,- O -isopropylidene-1- O - p -tolylsulfonyl- L - threo -glycerol-1-yl)-1-phenyl-4,5-pyrazoledione 4-(phenylhydrazone). Benzoylation of the 2,3-isopropylidene acetal of 2 gave 3-(1- O -benzoyl-2,3- O -isopropylidene- L - threo -glycerol-1-yl)-1-phenyl-4,5-pyrazoledione 4-(phenylhydrazone) that, upon deacetalation, gave 3-(1- O -benzoyl- L - threo -glycerol-1-yl)-1-phenyl-4,5-pyrazoledione 4-(phenylhydrazone), benzoylated to 1-phenyl-3-(1,2,3-tri- O -benzoyl- L - threo -glycerol-1-yl)-4,5-pyrazoledione 4-(phenylhydrazone). Debenzoylation followed by periodate oxidation gave the same aldehyde, 3-formyl-1-phenyl-4,5-pyrazoledione 4-(phenylhydrazone), as was obtained on similar treatment of 2 . Bromination of 2 afforded 1-( p -bromophenyl)-3-( L - threo -glycerol-1-yl)-4,5-pyrazoledione 4-( p -bromophenyl)-hydrazone, and that gave a monoisopropylidene acetal. The structures of these compounds were confirmed by i.r. spectroscopy.

Controlled reaction of L - threo -2,3-hexodiulosono-1,4-lactone with substituted phenylhydrazines gave the 2-(monoarylhydrazones) ( 2 ), which underwent dehydrative acetylation to 4-(2-acetoxyethylidene)-4-hydroxy-2,3-dioxohutyro-1,4-lactone 2-(2-arylhydrazones) ( 3 ). The latter reacted with methylhydrazine to give 1-methyl-3-(1-methylpyrazolin-3-yl)-4,5-pyrazoledione 4-(2-arylhydrazones) ( 4 ). Reaction of the monoarythydrazones ( 2 ) with phenylhydrazine gave the mixed bishydrazones ( 5 ), which were rearranged by alkali and acidification to the pyrazolediones ( 6 ). Compounds 6 gave triacetyl ( 7 ) and tribenzoyl derivatives ( 8 ), and, on periodite oxidation, the aldehydes ( 9 ), which afforded the monohydrazones ( 10 ). The i.r.. n.m.r.. and mass-spectral data of some of the compounds were investigated.

The 1-methyl derivatives ( 3 and 4 ) of 3-(1-phenyl- ( 1 ) and 3-(1- p -bromophenylhydrazono- L - threo -2,3,4-trihydroxybutyl)-2-quinoxalinone ( 2 ) were prepared by methylation. Periodate oxidation of 3 gave 1-methyl-3-[1-(phenylhydrazono)glyoxal-1-yl]-2-quinoxalinone ( 5 ), which, on reduction with sodium borohydride, gave the corresponding 3-[2-hydroxy-1-(phenylhydrazono)ethyl] derivative ( 8 ). Reaction of 5 with hydroxylamine or benzoylhydrazine gave the corresponding 2-oxime ( 6 ) and 2-(benzoylhydrazone) ( 7 ), respectively. Acetic anhydride causes one molecule of 3 or 4 to undergo elimination of two molecules of water, with simultaneous acetylation and ring closure to afford pyrazoles 9 and 10 , respectively. Pyrolysis of the triacetate of 3 led to the elimination of acetic acid from the sugar and the hydrazone residue, to give the 3-[5-(acetoxymethyl)-1-phenylpyrazol-3-yl] derivatives ( 9 ). Acetic acid was found to effect the same rearrangement, but without acetylation, of 1 , 2 , and 3 to give the 3-[5-(hydroxymethyl)] derivatives 11 , 12 , and 13 , respectively. The structure of these pyrazoles was confirmed by a series of reactions, including methylation and acetylation. The n.m.r. and i.r. spectra of the compounds were investigated.

The isopropylidenation of 1-aryl-(-threo-glycerol-1-yl)-6,7-dimethyl-pyrazolo[3,4-b] quinoxaline gave regioselectively the corresponding α-threo-dioxolanes. The role of configuration of the glycerolyl residue in directing the location of the isopropylidene ring is discussed. Although the pyrazolo-quinoxaline ring was shown not to affect the regioselectivity, it has a considerable effect on the chemical shift of the methyl groups of the isopropylidene ring.

The mono- and bis-(p-fluorophenyl)hydrazones of dehydro-L-ascorbic acid were prepared. Oxidation of the bis(hydrazone) afforded 3,6-anhydro-3-C-(p-fluorophenylazo) L-xylo-2-hexul osono-1,4-1 actone-2-(p-fluorophenyl)hydrazone. Rearrangement of the bis(hydrazone) gave T-(p-fluorophenyl)-3-(L-threo-glycerol-1-yl)-pyrazoli n-4,5-di one-4-(p-fluorophenyl)hydrazone, whose periodate oxidation gave 3-formyl-1-(p-fluorophenyl pyrazol in-4.5-dione-3-4-(p-fluorophenyl)hydrazone that upon reduction gave 1-(p-fluorophenyl)-3-hydroxymethyl pyrazol in-4,5-dione-4-(p-fluorophenyl)hydrazone. The compounds were characterized as their acetates and benzoates.

The mixed bis(arylhydrazones) of l - threo -2,3-hexodiulosono-1,4-lactone rearrange into pyrazolediones. Mono- and bis-(arylhydrazones) of isoascorbic acid were prepared; the latter are present in two forms that afford the same pyrazoledione. Acetylation, benzoylation, and periodate oxidation of these pyrazolediones were studied, and some condensation products from the pyrazole aldehyde were prepared. Some of the i.r. and mass-spectral data were discussed.

Oxidative cyclization of D-galactose (p-chlorophenyl)thiosemicarbazone gave 2-(p-chloroanilino)-5-(D-galacto-1,2,3,4,5-pentahydroxypentyl)-1,3,4-thiadiazole (1), whose acetylation afforded 2-[N-acetyl-N-(p-chlorophenyl)]-amino-5-(D-galacto-1,2,3,4,5-pentacetoxypentyl)- 1,3,4-thiadiazole (3). Its periodate oxidation of the glycol groups gave 2-(p-chloroanilino)-1,3,4-thiadiazole-5-carboxaldehyde (4), which can be transformed into 1,2-[2-(p-chloroanilino)-1,3,4-thiadiazol-5-yl]-1-hydroxy-2-oxoethane. A number of hydrazones of the formyl thiadiazole was prepared and its reduction with sodium borohydride gave 2-(p-chloroanilino)-5-hydroxymethyl-1,3,4-thiadiazole (6), whose acetylation gave a mono-O-acetyl derivative (7). Oxidation of the formyl thiadiazole gave 2-(p-chloroanilino)-1,3,4-thiadiazole (9). The spectral data of the compounds were discussed.

Isopropylidenation of 1-aryl-3-(-erythro-glycerol-1-yl)-6,7-dimethylflavazoles under thermodyanmically controlled conditions occurred regiosel ectively to give products having α-terminal isopropylidene rings. The role of the steric orientation of the hydroxyl groups on the regiosel ectivity was discussed. The location of the isopropylidene ring was confirmed by acylation and by studying the spectra of the products. The difference in the chemical shift (Δδ) between the proton resonances of the two methyl groups of the isopropylidene ring agreed with the shift rule of El Ashry.

X-ray crystallographic data show that the product obtained in the reaction of 4-(2-acetoxy-ethylidene)-4-hydroxy-2,3-dioxobutyro-1,4-lactone-2-(p-bromophenylhydrazone) with methyl-hydrazine is the bicyclic compound 2,6-dimethyl-3,4-dioxo-2,3,4,6,7,8-hexahydropyridazino-[4,3-c]pyridazine 4-(p-bromophenylhydrazone) (10) and not as originally suggested 1-methyl-3-(1-methylpyrazolin-3-yl)-4,5-pyrazoledione 4-(p-bromophenylhydrazone) (8).