IMB-SD62, a triazolothiadiazoles derivative with promising action against tuberculosis

Tuberculosis Drug Discovery: Challenges and New Horizons

“… Compound 93 exhibited a MIC value of 4.8 μM against Mtb H37Rv and an IC 50 value of 29 μM against Mtb SD; it also showed low cytotoxicity toward HepG2 cells (CC 50 50 μM). Moreover, in a BALB/c mouse model of acute Mtb infection, oral dosing of 93 at 50 mg/kg for 15 days reduced the bacterial lung load by 1.7 log 10 CFU, relative to the untreated control group . Nevertheless, further lead profiling studies exposed several deficiencies in 93 .…”

“…In 2018, Deng et al reported additional assessments of IMB-SD62 (93) (Figure 10), 235 a novel Mtb SD inhibitor, selected from a set of triazolothiadiazoles that the team had prepared earlier (based on the target-based HTS hit 92; Figure 10). 236 Compound 93 exhibited a MIC value of 4.8 μM against Mtb H37Rv and an IC 50 value of 29 μM against Mtb SD; it also showed low cytotoxicity toward HepG2 cells (CC 50 50 μM).…”

Mycobacterium tuberculosis Shikimate Pathway Enzymes as Targets for the Rational Design of Anti-Tuberculosis Drugs

“…There are three other reports on triazolothiadiazole inhibition of MtSD presented IC50 values ranging from ~7 μg/mL to ~5 mg/mL and MIC values ranging from 0.25 to 8 μg/mL [111][112][113]. One of the drugs (named IMB-SD62) showed in vitro activity against MDR-TB and in vivo anti-TB activity with a 1.7 log reduction in the CFUs in lungs and a preliminary pharmacokinetic study was performed demonstrating some potential for this class of molecules [113]. They display different inhibition mechanisms, which is valuable as they can turn into scaffolds for the design of several inhibition strategies against SD enzymes.…”

“…Multiple SD inhibitors have been reported with IC50 values ranging from ~3 to ~900 μM [101,[107][108][109][110], with only two reports showing MIC values of ~500 μM for a polyphenolic compound against P. putida [108] or shikimic acid derivatives against E. coli [109] and virtual screening derived compounds against S. aureus SD with Ki values ranging from ~8 to ~100 μM [101,110]. There are three other reports on triazolothiadiazole inhibition of MtSD presented IC50 values ranging from ~7 μg/mL to ~5 mg/mL and MIC values ranging from 0.25 to 8 μg/mL [111][112][113]. One of the drugs (named IMB-SD62) showed in vitro activity against MDR-TB and in vivo anti-TB activity with a 1.7 log reduction in the CFUs in lungs and a preliminary pharmacokinetic study was performed demonstrating some potential for this class of molecules [113].…”

An insight on medicinal attributes of 1,2,4-triazoles

“…SAR of triazolothiadiazines 185 regarding anti-TB activity led to the identification of two highly potent compounds 185a (MIC for Mtb H 37 Rv, DR-TB and MDR-TB strains: 0.25, 0.25 and 2.0 μg/mL) and 185b (MIC for Mtb H 37 Rv, DR-TB and MDR-TB strains: 1.0, 2.0 and 4.0 μg/mL) which were endowed with potent Mtb SD inhibitory properties with IC 50 values 86.39 and 73.57 μg/mL, respectively. Triazolothiadiazole IMB-SD62 184c , inhibitor of Mtb SD, showed in vivo anti-TB activity against acute Mtb H 37 Rv infection in mice with a 1.7 log reduction in the lung CFU counts and 14% oral bioavailability in a preliminary pharmacokinetic study [ 165 ].…”