Synthesis and characterization of the precursor compounds of a phenolic and pyrazinamide derivative of imidazo[2,1-b][1,3,4]thiadiazole and the evaluation of its predicted absorption, distribution, metabolism, and excretion (ADME) properties

Tuberculosis (TB) is an infectious disease that has continued to plague society and has caused the mortality of 1.3 million people worldwide in 2022. Among the various approved anti-TB drugs, pyrazinamide (PZA) possesses the unique ability to kill certain semi-dormant TB bacteria that other drugs fail to kill. However, with the continuous development of drug-resistant TB strains, modern TB treatment becomes difficult as conventional anti-TB drugs are left ineffective against these strains. Consequently, new therapeutics are warranted to overcome these resistant strains and to improve therapeutic efficacy. Thus, imidazothiadiazole derivatives have been widely explored due to the vast biological properties that it possesses, including anti-TB properties. Meanwhile, phenolic compounds have also been found to have antimicrobial and antioxidant activities. Their coupling with anti-TB drugs could present promising effects in treating TB. Hence, this study focused on the synthesis and characterization of the precursor compounds towards a new phenolic and pyrazinamide derivative of imidazo[2,1-b][1,3,4]thiadiazole. The final compound was evaluated on its potential as an orally bioavailable tuberculosis drug via its absorption, distribution, metabolism, and excretion (ADME) properties. Optimization methods were explored for the synthesis of the target compound, (E/Z)-N\u27-((6-(4-chlorophenyl)-2-(4-hydroxyphenyl)imidazo[2,1-b]- [1,3,4]thiadiazol-5-yl)methylene)pyrazine-2-carbohydrazide, involving a five-step process, with a phenolic group attached at the C-2 position, a PZA moiety at the C-5 position, and a 4-chlorophenyl group at the C-6 position of the imidazo[2,1- b][1,3,4]thiadiazole core. These optimizations led to the generation of the precursors to the target compound: 1. (E/Z)-2-(4-hydroxybenzylidene)hydrazine-1-carbothioamide (89.13%), 2. 4-(5-amino-1,3,4-thiadiazol-2-yl)phenol (83.83%), 3. [6-(4-chlorophenyl)imidazo[2,1-b]-1,3,4-thiadiazol-2-yl]phenol (43.21%), 4. [6-(4-chlorophenyl)imidazo[2,1-b]-1,3,4-thiadiazol-2-yl]phenol (68.08%). The ADME properties of the target compound exhibited a satisfactory pharmacokinetic profile fit for oral bioavailability. Thus, further investigations must be done for the viable synthesis method for the generation of the target compound. Moreover, biological assays may be conducted to further assess the potential synergistic effect of its antioxidant and anti-TB properties