Synthesis, Antimicrobial, and Anti-inflammatory Activities of Novel 2-[3-(1-Adamantyl)-4-substituted-5-thioxo-1,2,4-triazolin-1-yl]acetic Acids, 2-[3-(1-Adamantyl)-4-substituted-5-thioxo-1,2,4-triazolin-1-yl]propionic Acids and Related Derivatives

Abstract

The reaction of 3-(1-adamantyl)-4-substituted-1,2,4-triazoline-5-thiones 3a-g with sodium chloroacetate, in ethanolic sodium hydroxide yielded the corresponding N1-acetic acid derivatives 4a-g. The interaction of 3a-g with ethyl 2-bromopropionate in acetone, in the presence of potassium carbonate, yielded the corresponding N1-ethyl propionate derivatives 5a-g, which upon hydrolysis with aqueous sodium hydroxide afforded the corresponding propionic acid derivatives 6a-g. Similarly, the reaction of 3-(1-adamantyl)-4-amino-1,2,4-triazoline-5-thione 7 with sodium chloroacetate in ethanolic sodium hydroxide yielded the corresponding N1-acetic acid derivative 8. On the other hand, the reaction of 2-(1-adamantyl)-1,3,4-oxadiazoline-5-thione 9 with sodium chloroacetate yielded the corresponding S-acetic acid derivative 10. Compounds 4a-g, 5b, 5c, 5g, 6a-g, 8 and 10 were tested for in vitro activities against a panel of Gram-positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans. Several derivatives produced good or moderate activities particularly against Bacillus subtilis. In addition, the in vivo anti-inflammatory activities of these compounds were determined using the carrageenin-induced paw oedema method in rats. Compounds 4a, 4b, 4e, 4f, 6f, 6g and 10 produced good dose-dependent anti-inflammatory activities.

Synthesis and Antioxidant Activity Evaluation of New Compounds from Hydrazinecarbothioamide and 1,2,4-Triazole Class Containing Diarylsulfone and 2,4-Difluorophenyl Moieties

“…In 13 C-NMR of compounds 7 – 9 the C-3 and C-5 heterocyclic carbon from triazole nucleus resonated at 169.52–169.54 and 149.01–149.03 ppm, respectively. The signal of the C-3 quaternary carbon atom at ~169 ppm is characteristic of C=S group [12,13,41,42,43] which indicates the presence of the thione tautomeric form in solution. The most significant proof of the alkylation of triazoles 7 – 9 with 2-bromoacetophenone or 2-bromo-4'-fluoroacetophenone was the presence in 13 C-NMR spectra of compounds 10 – 12 and 13 – 15 of two new signals at 191.42–192.73 and 40.33–40.46 ppm corresponding to C=O and S-CH 2 carbon atoms from a phenacyl/4-fluorophenacyl group.…”

“…In addition, the formation of S-alkylated and not of N -alkylated products was confirmed by the absence of a C=S characteristic peak at ~169 ppm in 13 C-NMR spectra of 10 – 15 . The C-3 and C-5 heterocyclic carbons from these alkylated compounds resonate at 153.09–153.16 ppm (more shielded than the C-3 heterocyclic carbon from 1,2,4-triazoles 7 – 9 ) and 153.01–153.09 ppm, respectively [12,43,44]. …”

Antimicrobial and Hypoglycemic Activities of Novel N-Mannich Bases Derived from 5-(1-Adamantyl)-4-substituted-1,2,4-triazoline-3-thiones

“…The synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid CD437 (VI) was discovered as a potent inducer of apoptosis in human head and neck squamous cell carcinoma [ 13 ]. Several adamantane derivatives were recognized as potent bactericidal and fungicidal agents [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. SQ109 (VII) was approved for use against drug-susceptible and drug-resistant tuberculosis strains [ 23 ].…”

“…MK-544 (XII) [ 32 ], PF-877423 (XIII) [ 33 ], AZD6925 (XIV) [ 34 ], are recently developed drug candidates for the treatment of non-insulin-dependent diabetes and obesity. Moreover, anti-inflammatory activity was reported in several adamantane-containing molecules [ 19 , 20 , 21 , 22 , 35 , 36 , 37 , 38 ]. Arterolane (XV) [ 39 ], adaprolol (XVI) [ 40 ] and DS-8108b (XVII) [ 41 ] are recently developed adamantane-containing drugs for the treatment of malaria, glaucoma and hypertension, respectively.…”

Synthesis, antimicrobial, and anti-inflammatory activity, of novel S-substituted and N-substituted 5-(1-adamantyl)-1,2,4-triazole-3-thiols

“…This has resulted in the discovery of several drugs which are now available on market. Antiviral,3–13 antidiabetic,14 antimicrobial,15–23 anti-inflammatory,21–26 and central nervous system activities27–29 are the most important biological activities of adamantane derivatives. In addition, several 1,2,4-triazoles and their N -Mannich bases were reported to possess potent antimicrobial30–33 and anti-inflammatory34–36 activities.…”