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1.
ACS Med Chem Lett ; 10(10): 1480-1485, 2019 Oct 10.
Article in English | MEDLINE | ID: mdl-31620237

ABSTRACT

We report a novel benzimidazole (BI) based DprE1 inhibitor that resulted from scaffold morphing of a 1,4-azaindole series. The clinical progression of the 1,4-azaindole series from our previous work validates the potential of exploring newer chemical entities with antimycobacterial activity driven via a noncovalent inhibition of the decaprenylphosphoryl-ß-d-ribose-2'-epimerase (DprE1). The representative compounds from the new scaffold reported in this study exhibited an improved solubility and higher free plasma fraction, while retaining potent DprE1 inhibition and antimycobacterial activity. A representative compound from the benzimidazole series demonstrated good efficacy in a murine model of tuberculosis. Furthermore, molecular modeling of the BI scaffold suggests plausible modes of binding in the active site of DprE1 enzyme from Mycobacterium tuberculosis that can be used for further exploration of the series.

2.
J Med Chem ; 60(4): 1379-1399, 2017 02 23.
Article in English | MEDLINE | ID: mdl-28075132

ABSTRACT

The approval of bedaquiline to treat tuberculosis has validated adenosine triphosphate (ATP) synthase as an attractive target to kill Mycobacterium tuberculosis (Mtb). Herein, we report the discovery of two diverse lead series imidazo[1,2-a]pyridine ethers (IPE) and squaramides (SQA) as inhibitors of mycobacterial ATP synthesis. Through medicinal chemistry exploration, we established a robust structure-activity relationship of these two scaffolds, resulting in nanomolar potencies in an ATP synthesis inhibition assay. A biochemical deconvolution cascade suggested cytochrome c oxidase as the potential target of IPE class of molecules, whereas characterization of spontaneous resistant mutants of SQAs unambiguously identified ATP synthase as its molecular target. Absence of cross resistance against bedaquiline resistant mutants suggested a different binding site for SQAs on ATP synthase. Furthermore, SQAs were found to be noncytotoxic and demonstrated efficacy in a mouse model of tuberculosis infection.


Subject(s)
Adenosine Triphosphate/metabolism , Antitubercular Agents/therapeutic use , Mycobacterium tuberculosis/drug effects , Pyridines/therapeutic use , Quinine/analogs & derivatives , Tuberculosis/drug therapy , Animals , Antitubercular Agents/chemistry , Antitubercular Agents/pharmacokinetics , Antitubercular Agents/pharmacology , Ethers/chemistry , Ethers/pharmacokinetics , Ethers/pharmacology , Ethers/therapeutic use , Humans , Mice , Mice, Inbred BALB C , Models, Molecular , Pyridines/chemistry , Pyridines/pharmacokinetics , Pyridines/pharmacology , Quinine/chemistry , Quinine/pharmacokinetics , Quinine/pharmacology , Quinine/therapeutic use , Tuberculosis/metabolism
3.
Bioorg Med Chem ; 23(24): 7694-710, 2015 Dec 15.
Article in English | MEDLINE | ID: mdl-26643218

ABSTRACT

We report the discovery of benzothiazoles, a novel anti-mycobacterial series, identified from a whole cell based screening campaign. Benzothiazoles exert their bactericidal activity against Mycobacterium tuberculosis (Mtb) through potent inhibition of decaprenylphosphoryl-ß-d-ribose 2'-oxidase (DprE1), the key enzyme involved in arabinogalactan synthesis. Specific target linkage and mode of binding were established using co-crystallization and protein mass spectrometry studies. Most importantly, the current study provides insights on the utilization of systematic medicinal chemistry approaches to mitigate safety liabilities while improving potency during progression from an initial genotoxic hit, the benzothiazole N-oxides (BTOs) to the lead-like AMES negative, crowded benzothiazoles (cBTs). These findings offer opportunities for development of safe clinical candidates against tuberculosis. The design strategy adopted could find potential application in discovery of safe drugs in other therapy areas too.


Subject(s)
Alcohol Oxidoreductases/metabolism , Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Bacterial Proteins/metabolism , Benzothiazoles/chemistry , Benzothiazoles/pharmacology , Mycobacterium tuberculosis/drug effects , Mycobacterium tuberculosis/enzymology , Alcohol Oxidoreductases/antagonists & inhibitors , Bacterial Proteins/antagonists & inhibitors , Drug Design , Humans , Molecular Docking Simulation , Structure-Activity Relationship , Tuberculosis/drug therapy , Tuberculosis/microbiology
4.
Bioorg Med Chem Lett ; 25(16): 3234-45, 2015 Aug 15.
Article in English | MEDLINE | ID: mdl-26087937

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(1H)-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.


Subject(s)
Antitubercular Agents/pharmacology , Piperidines/pharmacology , Spiro Compounds/pharmacology , Animals , Antitubercular Agents/chemical synthesis , Antitubercular Agents/pharmacokinetics , Bacteria/drug effects , Drug Resistance, Bacterial/genetics , Genome, Bacterial , High-Throughput Screening Assays , Hypoxia , Lipids/chemistry , Matrix Metalloproteinase 13/biosynthesis , Matrix Metalloproteinase 13/genetics , Mice , Microbial Sensitivity Tests , Mycobacterium tuberculosis/drug effects , Mycobacterium tuberculosis/genetics , Piperidines/chemical synthesis , Piperidines/pharmacokinetics , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacokinetics , Structure-Activity Relationship
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