Whole cell screen based identification of spiropiperidines with potent antitubercular properties. Issue 16 (15th August 2015)

• Record Type: Journal Article
• Authors: Tantry, Subramanyam J.; Degiacomi, Giulia; Sharma, Sreevalli; Jena, Lalit kumar; Narayan, Ashwini; Guptha, Supreeth; Shanbhag, Gajanan; Menasinakai, Sreenivasaiah; Mallya, Meenakshi; Awasthy, Disha; Balakrishnan, Gayathri; Kaur, Parvinder; Bhattacharjee, Deepa; Narayan, Chandan; Reddy, Jitendar; Naveen Kumar, C.N.; Shandil, Radha; Boldrin, Francesca; Ventura, Marcello; Manganelli, Riccardo; Hartkoorn, Ruben C.; Cole, Stewart T.; Panda, Manoranjan; Markad, Shankar D.; Ramachandran, Vasanthi; Ghorpade, Sandeep R.; Dinesh, Neela
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 16(2015)
• Page Start: 3234
• Page End: 3245
• Publication Date: 2015-08-15
• Subjects: Whole cell screen -- ss18b -- Antimycobacterial -- Non-replicating phase -- Hypoxic conditions -- MmpL3; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.05.087
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Whole cell based screens to identify hits against Mycobacterium tuberculosis (Mtb), carried out under replicating and non-replicating (NRP) conditions, resulted in the identification of multiple, novel but structurally related spiropiperidines with potent antitubercular properties. These compounds could be further classified into three classes namely 3-(3-aryl-1, 2, 4-oxadiazol-5-yl)-1′-alkylspiro[indene-1, 4′-piperidine] (abbr. spiroindenes), 4-(3-aryl-1, 2, 4-oxadiazol-5-yl)-1′-alkylspiro[chromene-2, 4′-piperidine] (abbr. spirochromenes) and 1′-benzylspiro[indole-1, 4′-piperidin]-2(1 H )-one (abbr. spiroindolones). Spiroindenes showed ⩾4 log10 kill (at 2–12 μM) on replicating Mtb, but were moderately active under non replicating conditions. Whole genome sequencing efforts of spiroindene resistant mutants resulted in the identification of I292L mutation in MmpL3 (Mycobacterial membrane protein Large), required for the assembly of mycolic acid into the cell wall core of Mtb. MIC modulation studies demonstrated that the mutants were cross-resistant to spirochromenes but not to spiroindolones. This Letter describes lead identification efforts to improve potency while reducing the lipophilicity and hERG liabilities of spiroindenes. Additionally, as deduced from the SAR studies, we provide insights regarding the new chemical opportunities that the spiroindolones can offer to the TB drug discovery initiatives.