Abstract
The reaction of 1-adamantyl isothiocyanate 4 with the various cyclic secondary amines yielded the corresponding N-(1-adamantyl)carbothioamides 5a–e, 6, 7, 8a–c and 9. Similarly, the reaction of 4 with piperazine and trans-2,5-dimethylpiperazine in 2:1 molar ratio yielded the corresponding N,N'-bis(1-adamantyl)piperazine-1,4-dicarbothioamides 10a and 10b, respectively. The reaction of N-(1-adamantyl)-4-ethoxycarbonylpiperidine-1-carbothioamide 8c with excess hydrazine hydrate yielded the target carbohydrazide 11, in addition to 4-(1-adamantyl)thiosemicarbazide 12 as a minor product. The reaction of the carbohydrazide 11 with methyl or phenyl isothiocyanate followed by heating in aqueous sodium hydroxide yielded the 1,2,4-triazole analogues 14a and 14b. The reaction of the carbohydrazide 11 with various aromatic aldehydes yielded the corresponding N'-arylideneamino derivatives 15a–g. The compounds 5a–e, 6, 7, 8a–c, 9, 10a, 10b, 14a, 14b and 15a–g were tested for in vitro antimicrobial activity against certain strains of pathogenic Gram-positive and Gram-negative bacteria and the yeast-like fungus Candida albicans. The compounds 5c, 5d, 5e, 6, 7, 10a, 10b, 15a, 15f and 15g showed potent antibacterial activity against one or more of the tested microorganisms. The oral hypoglycemic activity of compounds 5c, 6, 8b, 9, 14a and 15b was determined in streptozotocin (STZ)-induced diabetic rats. Compound 5c produced significant reduction of serum glucose levels, compared to gliclazide.
Highlights
IntroductionThe incorporation of an adamantyl moiety into several molecules results in compounds with relatively high lipophilicity, which in turn can modify the biological availability of these molecules
Derivatives of adamantane have long been known for their multifarious pharmacological activities.The incorporation of an adamantyl moiety into several molecules results in compounds with relatively high lipophilicity, which in turn can modify the biological availability of these molecules
1-adamantylamine 1 was reacted with carbon disulfide and trimethylamine, in ethanol, to yield the dithiocarbamate salt 2, followed by addition of di-tert-butyl dicarbonate (Boc2O) to yield the intermediate 3, which was converted to the target product 4 via stirring with catalytic amount of 4-dimethylaminopyridine (DMAP). 1-Adamantyl isothiocyanate 4 was reacted with the cyclic secondary amines namely, 1-substituted piperazines, morpholine, pyrrolidine, 4-substituted piperdines and 1,2,3,4-tetrahydroisoquinoline, in boiling ethanol, to yield the corresponding N-(1-adamantyl)carbothioamides 5a–e, 6, 7, 8a–c and 9, respectively
Summary
The incorporation of an adamantyl moiety into several molecules results in compounds with relatively high lipophilicity, which in turn can modify the biological availability of these molecules. After the discovery of amantadine in 1960 as potent antiviral drug for the treatment of Influenza A infection [3–5] and as antiparkinsonian drug [6,7], adamantane derivatives attracted the attention of several scientists as potential chemotherapeutic agents. Further studies based on amantadine resulted in the discovery of more potent antiviral drugs as Rimantadine [8] and Tromantadine [9]. 6-[3-(1-Adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437), a synthetic retinoid derivative, was developed as a potent inducer of apoptosis in human head and neck squamous cell carcinoma [14]. The adamantane-based drugs, Vildagliptin [26] and Saxagliptin [27] are members of a new class of oral hypoglycemic agents known as dipeptidyl peptidase
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