Thiazole–aminopiperidine hybrid analogues: Design and synthesis of novel Mycobacterium tuberculosis GyrB inhibitors

An efficient synthesis and biological screening of benzofuran and benzo[ d ]isothiazole derivatives for Mycobacterium tuberculosis DNA GyrB inhibition

“…As previously reported these hydrophobic interactions contributed toward their specificity and bioactivity. 8 Figure 7. Overall, benzofuran derivatives, with some exceptions, can be considered as better GyrB inhibitors when compared to benzisothiazole ones.…”

“…We had previously designed and developed various classes of inhibitors as mycobacterial GyrB inhibitors utilizing the concept of molecular hybridization. 8 The preliminary structure-activity profiling studies of these leads provided valuable information regarding the basic structural requirements for achieving selective inhibition of mycobacterium GyrB. An imperative from our previous research efforts revealed the importance of hydrophobic interactions in bringing specificity toward the mycobacterial GyrB protein.…”

“…7 While the GyrA subunit has been well understood with most of the fluoroquinolones targeting it but not much has been explored on the GyrB subunit except one approved antibiotic, novobiocin that has been withdrawn from the market due to severe safety concern and poor pharmacological properties. 8 Moreover, GyrB has been genetically demonstrated to be a bactericidal drug target in MTB, but till date there have not been any effective therapeutics developed against this target for TB which was why we made an attempt toward synthesis of a chemical class of molecules targeting the GyrB subunit. 9 In this study we disclose two novel classes of mycobacterial DNA gyrase B inhibitors developed via molecular hybridization of earlier reported GyrB leads.…”

Discovery of Novel Mycobacterial DNA Gyrase B Inhibitors: In Silico and In Vitro Biological Evaluation

“…Availability of crystal structure of M. smegmatics GyrB in complex with one of the aminopyrazinamides facilitated us to employ structure-based virtual screening approach to obtain new hits from a commercial library of Asinex database using energy-optimized pharmacophore modeling. Further the model was validated using enrichment calculations, and finally three models doles, [15] bithiazoles, [16] aminopyrazinamides, [17] N-linked aminopiperidine, [18] and thiazole-aminopiperidine [19] as potential hits. Despite quite successful progress with respect to the bacterial target, very little has been achieved when it comes to mycobacterial GyrB as a target.…”

Recent Developments and Biological Activities of 2-Aminothiazole Derivatives

“…19 These derivatives continue to attract the attention of biologists because of their widespread use in the treatment of the biological systems. For instance, many papers have been published on the use of these compounds exhibiting antimicrobial, [20][21][22] antifungal and anti-inflammatory activity, 23 anesthetic activity, 4,24 as antiviral drugs, 6 anti-leukemic agents, 25 antiproliferatives (cytostatic and cytotoxic) with activity against a panel of cell lines (HeLa, L929, HT-29 and T47D), 26 as active agents against some enzymes involved in eicosanoid metabolism (5-, 12-, 15-lipoxygenase (LO), cyclooxygenase-1 and -2 (COX-1 and COX-2)), 27 inhibitors anti-TCR antibody induced IL-2 production in mice in vivo and reduced lung inflammation in a mouse model of ovalbumin induced allergy/asthma, 28 inhibitors for Mycobacterium tuberculosis (Mtb, H37Rv and MS, GyrB), 29,30 as vascular adhesion protein-1 inhibitors (VAP-1), 31,32 inhibitors of Cdc7 kinase activity in cancer cells, 33 inhibitors of nerve growth factor receptor TrkA, 34 inhibitors of p38α mitogen-activated protein kinase (p38α MAPK). 35 They can also bind to CT-DNA by the intercalative and electrostatic binding mode.…”