Design, Synthesis, SAR and Molecular Modeling Studies of Novel Imidazo[2,1‐b][1,3,4]Thiadiazole Derivatives as Highly Potent Antimicrobial Agents

Abstract

In this study, a novel series of phenyl substituted imidazo[2,1-b][1,3,4]thiadiazole derivatives were synthesized, characterized and explored for antibacterial activity against Gram-negative Escherichia coli, Gram-positive Staphylococcus aureus and Bacillus subtilis and antifungal activity against Candida albicans. Most of the synthesized compounds exhibited remarkable antimicrobial activities, some of which being ten times more potent than positive controls. The most promising compound showed excellent activity with MIC value of 0.03 μg/ml against both S. aureus and B. subtilis (MIC values of positive compound Chloramphenicol are 0.4 μg/ml and 0.85 μg/ml, respectively). Furthermore, structure-activity relationship was also investigated with the help of computational tools. Some physicochemical and ADME properties of the compounds were calculated too. The combination of electronic structure calculations performed at PM6 level and molecular docking simulations using Glide extra-precision mode showed that the hydrophobic nature of keto aryl ring with no electron withdrawing substituents at para position enhances activity while electron-donating substituents at the second aryl ring is detrimental to activity.

Novel Substituted Imidazo[2,1‐b][1,3,4]Thiadiazole Derivatives: Synthesis, Characterization, Molecular Docking Study, and Investigation of Their In Vitro Antifungal Activities

“…Instead, C 5 –H signals were observed as a singlet corresponding to one proton in the 8.93–8.50 ppm range, which indicates ring cyclization and is the most important evidence for the formation of imidazo[2,1‐ b ][1,3,4]thiadiazole derivatives ( 4 – 16 ). These values are consistent with those of similar studies in the literature .…”

“…These heterocyclic systems, in which imidazole and 1,3,4‐thiadiazole rings are fused to each other with a bridgehead nitrogen atom, are referred to as imidazo[2,1‐ b ][1,3,4]thiadiazoles . Imidazo[2,1‐ b ][1,3,4]thiadiazoles and their derivatives are widely used in medicine, pharmaceutics, and pharmaceutical chemistry because of their numerous biological activities, including antimicrobial , antifungal , antibacterial , anti‐inflammatory, antitubercular , analgesic , and diuretic activities.…”

Synthesis of 1,3,4-Thiadiazole Derivatives and Microbiological Activities: A Review

“…Moreover, the heterocyclic compounds have been the focus of much research in the field of Medicinal Chemistry. 20,35,[75][76][77] Khalaj et al (2011) 78 The evaluated compounds presented MIC values similar to the reference antibiotic (linezolid -MIC> 100 μg/mL) for Pseudomonas aeruginosa and Escherichia coli. The assays employing Gram-negative bacteria presented MICs between 0.78 and 100 μg/mL.…”

Anti-biofilm Fe3O4@C18-[1,3,4]thiadiazolo[3,2-a]pyrimidin-4-ium-2-thiolate Derivative Core-shell Nanocoatings

“…Moreover, thiadiazole is a versatile substrate for designing a large diversity of fused heterocycles, such as those with triazole [ 29 , 30 , 31 , 32 , 33 , 34 ], imidazole [ 35 , 36 , 37 , 38 , 39 ], and pyrimidine [ 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ], most of them with confirmed biological activity.…”