Synthesis and Antioxidant Activity of Novel 5-amino-2-alkyl/glycosylthio-1,3,4- thiadiazoles: Regioselective Alkylation and Glycosylation of the 5-amino-1,3,4- thiadiazole-2-thiol Scaffold.

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.

Synthesis and X-ray analysis of butyl and glycosyl (2-arylamino-4,4-dimethyl-6-oxocyclohex-1-ene)carbodithioates and their possible cyclization to 2-thioxo-6,7-dihydro-1H-benzo[d][1,3]thiazin-5(2H)-one derivatives.

Variety of butyl [2-arylamino-4,4-dimethyl-6-oxo-cyclohex-1-ene]carbodithioates (3a-c), 2-thioxo-6,7-dihydro-1H-benzo[d][1,3]thiazin-5(2H)-one derivatives (5a-c), and the glucosyl carbodithioates 6a-c as well as galactosyl carbodithioates 7a-c have been synthesized from the reaction of enaminone derivatives 1a-c with carbon disulfide followed by the alkylation with n-butyl bromide and α-d-glycosyl bromides, respectively. The amount of carbon disulfide plays a great role in the mode of reaction. The structures of the synthesized compounds were elucidated by spectral data and X-ray crystallography.

Revisit to the reaction of o-phenylene diamine with thiosemicarbazide to give benzimidazole-2-thione rather than benzotriazine-2-thione and its glycosylation.

Reaction of o-phenylene diamine with thiosemicarbazide did not give benzotriazine-2-thione 2 as reported, although the product was found to be benzimidazole-2-thione 3. Glycosylation of 3 with acetobromo sugars 4a-4b gave the respective thioglycosides 7a-7d in addition to minor products of the nucleosides 8a and 8b, in the case of the gluco- and galacto-analogs, respectively. The regioselectivity of glycosylation reaction has been investigated.

n-Butyl 2-(2,4-dichloro-anilino)-4,4-dimethyl-6-oxocyclo-hex-1-enecarbo-dithio-ate.

The cyclo-hexene ring in the title compound, C(19)H(23)Cl(2)NOS(2), adopts an envelope conformation, with the C atom bearing the two methyl groups representing the flap. This atom deviates by 0.630 (2) Šfrom the plane passing through the other five atoms of the ring (r.m.s. deviation = 0.020 Å). The mol-ecular conformation is stabilized by an intra-molecular N-H⋯S hydrogen bond.

Benzyl 2-(4-bromo-anilino)-4,4-dimethyl-6-oxocyclo-hex-1-enecarbodithio-ate: first triclinic polymorph.

The six-membered cyclo-hexene ring in the title compound, C(22)H(22)BrNOS(2), adopts an envelope conformation, with the C atom bearing the two methyl groups representing the flap. This atom deviates by 0.686 (4) Šfrom the plane passing through the other five atoms of the ring (r.m.s. deviation = 0.025 Å). The mol-ecular conformation is stabilized by an intra-molecular N-H⋯S hydrogen bond.

Benzyl 2-(4-bromo-anilino)-4,4-dimethyl-6-oxo-cyclo-hex-1-enecarbodithio-ate: second triclinic polymorph.

The title structure, C(22)H(22)BrNOS(2), is a triclinic modification. Whereas the other reported modification crystallizes with just one mol-ecule in the asymmetric unit, the present modification has Z' = 2. The six-membered cyclo-hexene ring adopts an envelope conformation, with the C atom bearing the two methyl groups representing the flap. This atom deviates by 0.674 (4) Šfrom the plane passing through the other five atoms of the ring (r.m.s. deviation = 0.027 Å). For the second independent mol-ecule, the deviation is 0.669 (3) Šand the r.m.s. deviation is 0.010 Å. The mol-ecular conformation of both mol-ecules is stabilized by intra-molecular N-H⋯S hydrogen bonds.

n-Undeca-nyl 2-(4-chloro-anilino)-4,4-dimethyl-6-oxocyclo-hex-1-ene-carbo-dithio-ate.

The six-membered cyclo-hexene ring in the title compound, C(26)H(38)ClNOS(2), adopts an envelope conformation, with the C atom bearing the two methyl groups representing the flap. This atom deviates by 0.642 (4) Šfrom the plane passing through the other five atoms of the ring (r.m.s. deviation = 0.053 Å). The mol-ecular conformation is stabilized by an intra-molecular N-H⋯S hydrogen bond.

n-Undeca-nyl 2-(4-bromo-anilino)-4,4-dimethyl-6-oxocyclo-hex-1-ene-carbodithio-ate.

The six-membered cyclo-hexene ring in the title compound, C(26)H(38)BrNOS(2), adopts an envelope conformation, with the C atom bearing the two methyl groups representing the flap. This atom deviates by 0.651 (3) Šfrom the plane passing through the other five atoms of the ring (r.m.s. deviation = 0.051 Å). The mol-ecular conformation is stabilized by an N-H⋯S hydrogen bond. The title compound is isomorphous with n-undeca-nyl 2-(4-chloro-anilino)-4,4-dimethyl-6-oxocyclo-hex-1-enecarbodithio-ate.

n-Undeca-nyl 2-(2,4-dichloro-anilino)-4,4-dimethyl-6-oxocyclo-hex-1-ene-carbo-dithio-ate.

The six-membered cyclo-hexene ring in the title compound, C(26)H(37)Cl(2)NOS(2), adopts an envelope-shaped conformation, with the C atom bearing the two methyl groups representing the flap. This atom deviates by 0.658 (7) Šfrom the plane passing through the other five atoms of the ring (r.m.s. deviation = 0.005 Å). The mol-ecular conformation is stabilized by an N-H⋯S hydrogen bond.

2-Hydroxy-ethyl 2-(2,4-dichloro-anilino)-4,4-dimethyl-6-oxocyclo-hex-1-ene-carbo-dithio-ate.

The six-membered cyclo-hexene ring in the title compound, C(17)H(19)Cl(2)NOS(2), adopts an envelope conformation, with the C atom bearing the two methyl groups representing the flap. This atom deviates by 0.716 (3) Šfrom the plane passing through the other five atoms of the ring (r.m.s. deviation = 0.072 Å). The mol-ecular conformation is stabilized by an intra-molecular N-H⋯S hydrogen bond. The hydr-oxy group engages in inter-molecular O-H⋯O hydrogen bonding with adjacent acceptor atoms to generate a zigzag chain running along the c axis.

2,3,4,6-Tetra-O-acetyl-ß-d-galacto-pyranosyl 2-(2,4-dichloro-anilino)-4,4-dimethyl-6-oxocyclo-hex-1-enecarbo-dithio-ate.

The cyclo-hexene ring in the title compound, C(29)H(33)Cl(2)NO(10)S(2), adopts an envelope conformation, with the C atom bearing the two methyl groups representing the flap. This atom deviates by 0.63 (1) Šfrom the plane through the other five ring atoms (r.m.s. deviation = 0.11 Å). The mol-ecular conformation is stabilized by an intra-molecular N-H⋯S hydrogen bond. The crystal studied was a non-merohedral twin, with a minor twin component of 29%.