Synthesis, molecular modeling and antioxidant screening of new thioether-bridged thiadiazole and thiadiazolopyrimidine analogues

Abstract

The N-aryl-2-((5-(2-cyanoacetamido)-1,3,4-thiadiazol-2-yl)thio)acetamide derivatives 3a-c were prepared and successfully reacted with N,N-dimethylformamide dimethyl acetal (DMF-DMA). The resulting N-thiadiazolyl-2-cyano-3-(dimethylamino)acrylamide derivatives 4a-c were cyclized in boiling acetic acid to yield the corresponding thiadiazolopyrimidine compounds 5a-c. The structural properties of synthesized compounds were studied using DFT/B3LYP level. The HOMO-LUMO energies were employed in determination of some chemical reactivity descriptors. Despite the close energy gap values (ΔEH-L) of the investigated compounds, the data showed that chloro derivatives has the highest energy gap while the methoxy derivatives were the lowest. The synthesized compounds were investigated to explore their antioxidant activities. The results showed that the N-thiadiazolyl-2-cyano-3-(dimethylamino)acrylamides 4a-c had higher inhibition IC50 values (24.27–31.64 µg/mL) than the thiadiazolyl cyanoacetamides 3a-c (34.26–39.33 µg/mL). However, thiadiazolopyrimidines 5a-c presented moderate inhibition with (IC50 = 40.21–44.19 µg/mL) in comparison to ascorbic acid and BHT (Butylated hydroxytoluene) as reference drugs with IC50 = 22.66 and 27.24 µg/mL, respectively. Furthermore, the synthesized compounds were evaluated against (PDB Code-3ML5) using the MOE operation v10.2015.10 database. The inspected synthesized thiadiazole derivatives 3, 4 and 5 revealed H-bond linkages over the receptor through the disparate polar amino acids (Thr 200, Thr 199, Gln 67, His 94, and Lys 91) of larger pocket size of 3ML5. The results of the docking study presented a remarkable agreement with the practical results of the antioxidant activity.