ABSTRACT
In search of novel drugs against tuberculosis, we previously discovered and profiled a novel hydantoin-based family that demonstrated highly promising in vitro potency against Mycobacterium. tuberculosis. The compounds were found to be noncovalent inhibitors of DprE1, a subunit of decaprenylphosphoryl-ß-d-ribose-2'-epimerase. This protein, localized in the periplasmic space of the mycobacterial cell wall, was shown to be an essential and vulnerable antimycobacterial drug target. Here, we report the further SAR exploration of this chemical family through more than 80 new analogues. Among these, the most active representatives combined submicromolar cellular potency and nanomolar target affinity with balanced physicochemical properties and low human cytotoxicity. Moreover, we demonstrate in vivo activity in an acute Mtb infection model and provide further proof of DprE1 being the target of the hydantoins. Overall, the hydantoin family of DprE1 inhibitors represents a promising noncovalent lead series for the discovery of novel antituberculosis agents.
Subject(s)
Alcohol Oxidoreductases/antagonists & inhibitors , Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Hydantoins/chemistry , Hydantoins/pharmacology , Alcohol Oxidoreductases/metabolism , Animals , Antitubercular Agents/metabolism , Bacterial Proteins/metabolism , Female , Hep G2 Cells , Humans , Hydantoins/metabolism , Mice , Mice, Inbred C57BL , Mycobacterium tuberculosis/drug effects , Mycobacterium tuberculosis/metabolism , Nuclear Magnetic Resonance, Biomolecular/methods , Tuberculosis/drug therapy , Tuberculosis/metabolismABSTRACT
Tuberculosis is the leading cause of death worldwide from infectious diseases. With the development of drug-resistant strains of Mycobacterium tuberculosis, there is an acute need for new medicines with novel modes of action. Herein, we report the discovery and profiling of a novel hydantoin-based family of antimycobacterial inhibitors of the decaprenylphospho-ß-d-ribofuranose 2-oxidase (DprE1). In this study, we have prepared a library of more than a 100 compounds and evaluated them for their biological and physicochemical properties. The series is characterized by high enzymatic and whole-cell activity, low cytotoxicity, and a good overall physicochemical profile. In addition, we show that the series acts via reversible inhibition of the DprE1 enzyme. Overall, the novel compound family forms an attractive base for progression to further stages of optimization and may provide a promising drug candidate in the future.
Subject(s)
Alcohol Oxidoreductases/antagonists & inhibitors , Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Hydantoins/chemistry , Actinobacteria/drug effects , Alcohol Oxidoreductases/metabolism , Bacterial Proteins/metabolism , Drug Stability , Enzyme Inhibitors/chemistry , Hep G2 Cells , High-Throughput Screening Assays/methods , Humans , Macrophages/microbiology , Microbial Sensitivity Tests , Mycobacterium tuberculosis/drug effects , Reproducibility of Results , Structure-Activity Relationship , Tuberculosis/drug therapy , Tuberculosis/microbiologyABSTRACT
Since the appearance of resistance to the current front-line antimalarial treatments, ACTs (artemisinin combination therapies), the discovery of novel chemical entities to treat the disease is recognized as a major global health priority. From the GSK antimalarial set, we identified an aminoxadiazole with an antiparasitic profile comparable with artemisinin (1), with no cross-resistance in a resistant strains panel and a potential new mode of action. A medicinal chemistry program allowed delivery of compounds such as 19 with high solubility in aqueous media, an acceptable toxicological profile, and oral efficacy. Further evaluation of the lead compounds showed that in vivo genotoxic degradants might be generated. The compounds generated during this medicinal chemistry program and others from the GSK collection were used to build a pharmacophore model which could be used in the virtual screening of compound collections and potentially identify new chemotypes that could deliver the same antiparasitic profile.
Subject(s)
2,2'-Dipyridyl/analogs & derivatives , Antimalarials/pharmacology , Oxadiazoles/pharmacology , 2,2'-Dipyridyl/administration & dosage , 2,2'-Dipyridyl/chemical synthesis , 2,2'-Dipyridyl/pharmacology , 2,2'-Dipyridyl/toxicity , Animals , Antimalarials/administration & dosage , Antimalarials/chemical synthesis , Antimalarials/toxicity , Atovaquone/pharmacology , Chloroquine/pharmacology , Drug Design , Female , Humans , Hydrazines/metabolism , Mice , Mutagenicity Tests , Mutagens/metabolism , Oxadiazoles/administration & dosage , Oxadiazoles/chemical synthesis , Oxadiazoles/toxicity , Parasitemia/drug therapy , Plasmodium falciparum/drug effects , Pyrimethamine/pharmacology , Structure-Activity RelationshipABSTRACT
Despite being one of the first antitubercular agents identified, isoniazid (INH) is still the most prescribed drug for prophylaxis and tuberculosis (TB) treatment and, together with rifampicin, the pillars of current chemotherapy. A high percentage of isoniazid resistance is linked to mutations in the pro-drug activating enzyme KatG, so the discovery of direct inhibitors (DI) of the enoyl-ACP reductase (InhA) has been pursued by many groups leading to the identification of different enzyme inhibitors, active against Mycobacterium tuberculosis (Mtb), but with poor physicochemical properties to be considered as preclinical candidates. Here, we present a series of InhA DI active against multidrug (MDR) and extensively (XDR) drug-resistant clinical isolates as well as in TB murine models when orally dosed that can be a promising foundation for a future treatment.
Subject(s)
Antitubercular Agents/pharmacology , Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Mycobacterium tuberculosis/drug effects , Mycobacterium tuberculosis/enzymology , Animals , Antitubercular Agents/chemistry , Binding Sites , Catalytic Domain , Disease Models, Animal , Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)/genetics , Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)/metabolism , Enzyme Inhibitors/chemistry , Female , Humans , Mice , Microbial Sensitivity Tests , Microsomes , Models, Molecular , Mutation , Mycobacterium tuberculosis/genetics , Protein Binding , Protein Conformation , Tuberculosis/drug therapy , Tuberculosis/microbiology , Tuberculosis/mortality , Tuberculosis, Multidrug-ResistantABSTRACT
In this study, a new series of more than 60 quinoline derivatives has been synthesized and evaluated against Mycobacterium tuberculosis (H37Rv). Apart from the SAR exploration around the initial hits, the optimization process focused on the improvement of the physicochemical properties, cytotoxicity, and metabolic stability of the series. The best compounds obtained exhibited MIC values in the low micromolar range, excellent intracellular antimycobacterial activity, and an improved physicochemical profile without cytotoxic effects. Further investigation revealed that the amide bond was the source for the poor blood stability observed, while some of the compounds exhibited hERG affinity. Compound 83 which contains a benzoxazole ring instead of the amide group was found to be a good alternative, with good blood stability and no hERG affinity, providing new opportunities for the series. Overall, the obtained results suggest that further optimization of solubility and microsomal stability of the series could provide a strong lead for a new anti-TB drug development program.
Subject(s)
Antitubercular Agents/pharmacology , Benzoxazoles/pharmacology , Drug Design , Mycobacterium tuberculosis/drug effects , Quinolines/pharmacology , Antitubercular Agents/chemical synthesis , Antitubercular Agents/chemistry , Benzoxazoles/chemical synthesis , Benzoxazoles/chemistry , Dose-Response Relationship, Drug , Humans , Microbial Sensitivity Tests , Molecular Structure , Quinolines/chemical synthesis , Quinolines/chemistry , Structure-Activity RelationshipABSTRACT
Tuberculosis (TB) is one of the world's oldest and deadliest diseases, killing a person every 20 s. InhA, the enoyl-ACP reductase from Mycobacterium tuberculosis, is the target of the frontline antitubercular drug isoniazid (INH). Compounds that directly target InhA and do not require activation by mycobacterial catalase peroxidase KatG are promising candidates for treating infections caused by INH resistant strains. The application of the encoded library technology (ELT) to the discovery of direct InhA inhibitors yielded compound 7 endowed with good enzymatic potency but with low antitubercular potency. This work reports the hit identification, the selected strategy for potency optimization, the structure-activity relationships of a hundred analogues synthesized, and the results of the in vivo efficacy studies performed with the lead compound 65.
Subject(s)
Antitubercular Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Drug Discovery , Mycobacterium tuberculosis/drug effects , Oxidoreductases/antagonists & inhibitors , Magnetic Resonance Spectroscopy , Microbial Sensitivity Tests , Mycobacterium tuberculosis/metabolism , Spectrometry, Mass, Electrospray IonizationABSTRACT
With the aim of fuelling open-source, translational, early-stage drug discovery activities, the results of the recently completed antimycobacterial phenotypic screening campaign against Mycobacterium bovis BCG with hit confirmation in M. tuberculosis H37Rv were made publicly accessible. A set of 177 potent non-cytotoxic H37Rv hits was identified and will be made available to maximize the potential impact of the compounds toward a chemical genetics/proteomics exercise, while at the same time providing a plethora of potential starting points for new synthetic lead-generation activities. Two additional drug-discovery-relevant datasets are included: a) a drug-like property analysis reflecting the latest lead-like guidelines and b) an early lead-generation package of the most promising hits within the clusters identified.
Subject(s)
Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Drug Discovery/methods , Mycobacterium bovis/drug effects , Mycobacterium tuberculosis/drug effects , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Databases, Pharmaceutical , Hep G2 Cells , High-Throughput Screening Assays , Humans , Microbial Sensitivity Tests , Tuberculosis/drug therapyABSTRACT
A series of Sordarin derivatives bearing alkyl substituted tetrahydrofuran rings fused to C3'-C4' bond of the sugar moiety have been prepared and their antifungal properties evaluated. Most of them show remarkable antifungal activity against Candida spp and Cryptococcus neoformans.