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1.
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
2.
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
3.
Tuberculosis (Edinb) ; 95(5): 589-98, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26073894

ABSTRACT

DNA topoisomerases perform the essential function of maintaining DNA topology in prokaryotes. DNA gyrase, an essential enzyme that introduces negative supercoils, is a clinically validated target. However, topoisomerase I (Topo I), an enzyme responsible for DNA relaxation has received less attention as an antibacterial target, probably due to the ambiguity over its essentiality in many organisms. The Mycobacterium tuberculosis genome harbors a single topA gene with no obvious redundancy in its function suggesting an essential role. The topA gene could be inactivated only in the presence of a complementing copy of the gene in M. tuberculosis. Furthermore, down-regulation of topA in a genetically engineered strain of M. tuberculosis resulted in loss of bacterial viability which correlated with a concomitant depletion of intracellular Topo I levels. The topA knockdown strain of M. tuberculosis failed to establish infection in a murine model of TB and was cleared from lungs in two months post infection. Phenotypic screening of a Topo I overexpression strain led to the identification of an inhibitor, thereby providing chemical validation of this target. Thus, our work confirms the attractiveness of Topo I as an anti-mycobacterial target.


Subject(s)
Antitubercular Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , DNA Topoisomerases, Type I , Drug Discovery , Mycobacterium tuberculosis/drug effects , Topoisomerase I Inhibitors/pharmacology , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , DNA Topoisomerases, Type I/genetics , DNA Topoisomerases, Type I/metabolism , Gene Expression Regulation, Bacterial , Gene Knockdown Techniques , Genotype , Humans , Microbial Viability , Molecular Targeted Therapy , Mycobacterium tuberculosis/enzymology , Mycobacterium tuberculosis/genetics , Mycobacterium tuberculosis/growth & development , Mycobacterium tuberculosis/pathogenicity , Phenotype , Time Factors
4.
Nat Commun ; 6: 6715, 2015 Mar 31.
Article in English | MEDLINE | ID: mdl-25823686

ABSTRACT

The widespread emergence of Plasmodium falciparum (Pf) strains resistant to frontline agents has fuelled the search for fast-acting agents with novel mechanism of action. Here, we report the discovery and optimization of novel antimalarial compounds, the triaminopyrimidines (TAPs), which emerged from a phenotypic screen against the blood stages of Pf. The clinical candidate (compound 12) is efficacious in a mouse model of Pf malaria with an ED99 <30 mg kg(-1) and displays good in vivo safety margins in guinea pigs and rats. With a predicted half-life of 36 h in humans, a single dose of 260 mg might be sufficient to maintain therapeutic blood concentration for 4-5 days. Whole-genome sequencing of resistant mutants implicates the vacuolar ATP synthase as a genetic determinant of resistance to TAPs. Our studies highlight the potential of TAPs for single-dose treatment of Pf malaria in combination with other agents in clinical development.


Subject(s)
Antimalarials/pharmacology , Plasmodium falciparum/drug effects , Pyrimidines/pharmacology , Amines/pharmacology , Animals , Drug Evaluation, Preclinical , Drug Resistance, Microbial , Guinea Pigs , Half-Life , Rats
5.
J Med Chem ; 57(13): 5702-13, 2014 Jul 10.
Article in English | MEDLINE | ID: mdl-24914738

ABSTRACT

Whole-cell high-throughput screening of the AstraZeneca compound library against the asexual blood stage of Plasmodium falciparum (Pf) led to the identification of amino imidazoles, a robust starting point for initiating a hit-to-lead medicinal chemistry effort. Structure-activity relationship studies followed by pharmacokinetics optimization resulted in the identification of 23 as an attractive lead with good oral bioavailability. Compound 23 was found to be efficacious (ED90 of 28.6 mg·kg(-1)) in the humanized P. falciparum mouse model of malaria (Pf/SCID model). Representative compounds displayed a moderate to fast killing profile that is comparable to that of chloroquine. This series demonstrates no cross-resistance against a panel of Pf strains with mutations to known antimalarial drugs, thereby suggesting a novel mechanism of action for this chemical class.


Subject(s)
Antimalarials/pharmacology , Benzimidazoles/therapeutic use , Malaria, Falciparum/drug therapy , Plasmodium falciparum/drug effects , Animals , Antimalarials/chemistry , Benzimidazoles/pharmacokinetics , Benzimidazoles/pharmacology , Biological Availability , Cell Line, Tumor , Cell Survival/drug effects , High-Throughput Screening Assays , Humans , Inhibitory Concentration 50 , Mice , Small Molecule Libraries , Structure-Activity Relationship
6.
J Med Chem ; 57(11): 4761-71, 2014 Jun 12.
Article in English | MEDLINE | ID: mdl-24818517

ABSTRACT

A novel pyrazolopyridone class of inhibitors was identified from whole cell screening against Mycobacterium tuberculosis (Mtb). The series exhibits excellent bactericidality in vitro, resulting in a 4 log reduction in colony forming units following compound exposure. The significant modulation of minimum inhibitory concentration (MIC) against a Mtb strain overexpressing the Rv3790 gene suggested the target of pyrazolopyridones to be decaprenylphosphoryl-ß-D-ribose-2'-epimerase (DprE1). Genetic mapping of resistance mutation coupled with potent enzyme inhibition activity confirmed the molecular target. Detailed biochemical characterization revealed the series to be a noncovalent inhibitor of DprE1. Docking studies at the active site suggest that the series can be further diversified to improve the physicochemical properties without compromising the antimycobacterial activity. The pyrazolopyridone class of inhibitors offers an attractive non-nitro lead series targeting the essential and vulnerable DprE1 enzyme for the discovery of novel antimycobacterial agents to treat both drug susceptible and drug resistant strains of Mtb.


Subject(s)
Antitubercular Agents/chemical synthesis , Bacterial Proteins/antagonists & inhibitors , Mycobacterium tuberculosis/drug effects , Oxidoreductases/antagonists & inhibitors , Pyrazoles/chemical synthesis , Pyridones/chemical synthesis , Alcohol Oxidoreductases , Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Bacterial Proteins/genetics , Catalytic Domain , Drug Resistance, Bacterial , Microbial Sensitivity Tests , Molecular Docking Simulation , Mutation , Mycobacterium tuberculosis/enzymology , Mycobacterium tuberculosis/isolation & purification , Oxidoreductases/genetics , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyridones/chemistry , Pyridones/pharmacology , Structure-Activity Relationship
7.
J Med Chem ; 57(12): 5419-34, 2014 Jun 26.
Article in English | MEDLINE | ID: mdl-24871036

ABSTRACT

4-Aminoquinolone piperidine amides (AQs) were identified as a novel scaffold starting from a whole cell screen, with potent cidality on Mycobacterium tuberculosis (Mtb). Evaluation of the minimum inhibitory concentrations, followed by whole genome sequencing of mutants raised against AQs, identified decaprenylphosphoryl-ß-d-ribose 2'-epimerase (DprE1) as the primary target responsible for the antitubercular activity. Mass spectrometry and enzyme kinetic studies indicated that AQs are noncovalent, reversible inhibitors of DprE1 with slow on rates and long residence times of ∼100 min on the enzyme. In general, AQs have excellent leadlike properties and good in vitro secondary pharmacology profile. Although the scaffold started off as a single active compound with moderate potency from the whole cell screen, structure-activity relationship optimization of the scaffold led to compounds with potent DprE1 inhibition (IC50 < 10 nM) along with potent cellular activity (MIC = 60 nM) against Mtb.


Subject(s)
Amides/chemistry , Antitubercular Agents/chemistry , Bacterial Proteins/antagonists & inhibitors , Mycobacterium tuberculosis/drug effects , Oxidoreductases/antagonists & inhibitors , Piperidines/chemistry , Quinolones/chemistry , Alcohol Oxidoreductases , Amides/pharmacokinetics , Amides/pharmacology , Animals , Antitubercular Agents/pharmacokinetics , Antitubercular Agents/pharmacology , Catalytic Domain , Cell Line, Tumor , Drug Resistance, Bacterial , Genome, Bacterial , Humans , Kinetics , Microbial Sensitivity Tests , Molecular Docking Simulation , Mutation , Mycobacterium tuberculosis/enzymology , Mycobacterium tuberculosis/genetics , Piperidines/pharmacokinetics , Piperidines/pharmacology , Protein Binding , Quinolones/pharmacokinetics , Quinolones/pharmacology , Rats, Wistar , Stereoisomerism , Structure-Activity Relationship
8.
J Med Chem ; 56(21): 8834-48, 2013 Nov 14.
Article in English | MEDLINE | ID: mdl-24088190

ABSTRACT

A pharmacophore-based search led to the identification of thiazolopyridine ureas as a novel scaffold with antitubercular activity acting through inhibition of DNA Gyrase B (GyrB) ATPase. Evaluation of the binding mode of thiazolopyridines in a Mycobacterium tuberculosis (Mtb) GyrB homology model prompted exploration of the side chains at the thiazolopyridine ring C-5 position to access the ribose/solvent pocket. Potent compounds with GyrB IC50 ≤ 1 nM and Mtb MIC ≤ 0.1 µM were obtained with certain combinations of side chains at the C-5 position and heterocycles at the C-6 position of the thiazolopyridine core. Substitutions at C-5 also enabled optimization of the physicochemical properties. Representative compounds were cocrystallized with Streptococcus pneumoniae (Spn) ParE; these confirmed the binding modes predicted by the homology model. The target link to GyrB was confirmed by genetic mapping of the mutations conferring resistance to thiazolopyridine ureas. The compounds are bactericidal in vitro and efficacious in vivo in an acute murine model of tuberculosis.


Subject(s)
Antitubercular Agents/pharmacology , DNA Gyrase/metabolism , Mycobacterium tuberculosis/drug effects , Pyridines/pharmacology , Topoisomerase II Inhibitors/pharmacology , Tuberculosis/drug therapy , Urea/pharmacology , Animals , Antitubercular Agents/administration & dosage , Antitubercular Agents/chemistry , Disease Models, Animal , Dose-Response Relationship, Drug , Mice , Mice, Inbred BALB C , Models, Molecular , Molecular Structure , Mycobacterium tuberculosis/enzymology , Pyridines/administration & dosage , Pyridines/chemistry , Structure-Activity Relationship , Topoisomerase II Inhibitors/administration & dosage , Topoisomerase II Inhibitors/chemistry , Urea/analogs & derivatives , Urea/chemistry
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