Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 10 de 10
Filter
Add more filters










Publication year range
2.
ACS Infect Dis ; 6(5): 1098-1109, 2020 05 08.
Article in English | MEDLINE | ID: mdl-32196311

ABSTRACT

In the course of optimizing a novel indazole sulfonamide series that inhibits ß-ketoacyl-ACP synthase (KasA) of Mycobacterium tuberculosis, a mutagenic aniline metabolite was identified. Further lead optimization efforts were therefore dedicated to eliminating this critical liability by removing the embedded aniline moiety or modifying its steric or electronic environment. While the narrow SAR space against the target ultimately rendered this goal unsuccessful, key structural knowledge around the binding site of this underexplored target for TB was generated to inform future discovery efforts.


Subject(s)
3-Oxoacyl-(Acyl-Carrier-Protein) Synthase/antagonists & inhibitors , Aniline Compounds/pharmacology , Mycobacterium tuberculosis , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Binding Sites , DNA Damage , Mycobacterium tuberculosis/enzymology
3.
J Med Chem ; 63(2): 591-600, 2020 01 23.
Article in English | MEDLINE | ID: mdl-31850752

ABSTRACT

New drugs that target Plasmodium species, the causative agents of malaria, are needed. The enzyme N-myristoyltransferase (NMT) is an essential protein, which catalyzes the myristoylation of protein substrates, often to mediate membrane targeting. We screened ∼1.8 million small molecules for activity against Plasmodium vivax (P. vivax) NMT. Hits were triaged based on potency and physicochemical properties and further tested against P. vivax and Plasmodium falciparum (P. falciparum) NMTs. We assessed the activity of hits against human NMT1 and NMT2 and discarded compounds with low selectivity indices. We identified 23 chemical classes specific for the inhibition of Plasmodium NMTs over human NMTs, including multiple novel scaffolds. Cocrystallization of P. vivax NMT with one compound revealed peptide binding pocket binding. Other compounds show a range of potential modes of action. Our data provide insight into the activity of a collection of selective inhibitors of Plasmodium NMT and serve as a starting point for subsequent medicinal chemistry efforts.


Subject(s)
Acyltransferases/antagonists & inhibitors , Antimalarials/chemical synthesis , Antimalarials/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Plasmodium/drug effects , Plasmodium/enzymology , Acyltransferases/chemistry , Animals , Binding Sites , Cell Line , Crystallography, X-Ray , Drug Discovery , High-Throughput Screening Assays , Humans , Malaria/drug therapy , Models, Molecular , Plasmodium falciparum/drug effects , Plasmodium vivax/drug effects , Small Molecule Libraries , Structure-Activity Relationship
4.
ACS Med Chem Lett ; 10(10): 1423-1429, 2019 Oct 10.
Article in English | MEDLINE | ID: mdl-31620228

ABSTRACT

In this study, a series of 49 five-membered heterocyclic compounds containing either a pyridine- or a pyrrole-type nitrogen were synthesized and tested against Mycobacterium tuberculosis. Among them, only the 1,3,5-trisubstituted pyrazoles 5-49 exhibited minimum inhibitory concentration values in the low micromolar range, and some also exhibited an improved physicochemical profile without cytotoxic effects. Three pyrazoles were subjected to an animal tuberculosis efficacy model, and compound 6 induced a statistically significant difference in lung bacterial counts compared with untreated mice. Moreover, to determine the target of this series, resistors were generated, and whole genome sequencing revealed mutations in the mmpL3 gene.

5.
Bioorg Med Chem Lett ; 28(22): 3529-3533, 2018 12 01.
Article in English | MEDLINE | ID: mdl-30316633

ABSTRACT

Previous work established a coumarin scaffold as a starting point for inhibition of Mycobacterium tuberculosis (Mtb) FadD32 enzymatic activity. After further profiling of the coumarin inhibitor 4 revealed chemical instability, we discovered that a quinoline ring circumvented this instability and had the advantage of offering additional substitution vectors to further optimize. Ensuing SAR studies gave rise to quinoline-2-carboxamides with potent anti-tubercular activity. Further optimization of ADME/PK properties culminated in 21b that exhibited compelling in vivo efficacy in a mouse model of Mtb infection.


Subject(s)
Antitubercular Agents/chemistry , Bacterial Proteins/antagonists & inhibitors , Coumarins/chemistry , Animals , Antitubercular Agents/metabolism , Antitubercular Agents/pharmacology , Antitubercular Agents/therapeutic use , Bacterial Proteins/metabolism , Disease Models, Animal , Drug Evaluation, Preclinical , Mice , Microbial Sensitivity Tests , Mycobacterium tuberculosis/drug effects , Mycobacterium tuberculosis/metabolism , Quinolines/chemistry , Structure-Activity Relationship , Tuberculosis/drug therapy , Tuberculosis/microbiology
6.
ChemMedChem ; 13(7): 672-677, 2018 04 06.
Article in English | MEDLINE | ID: mdl-29399991

ABSTRACT

Our findings reported herein provide support for the benefits of including functional group complexity (FGC) within fragments when screening against protein targets such as Mycobacterium tuberculosis InhA. We show that InhA fragment actives with FGC maintained their binding pose during elaboration. Furthermore, weak fragment hits with functional group handles also allowed for facile fragment elaboration to afford novel and potent InhA inhibitors with good ligand efficiency metrics for optimization.


Subject(s)
Antitubercular Agents/chemistry , Bacterial Proteins/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Mycobacterium tuberculosis/enzymology , Oxidoreductases/antagonists & inhibitors , Small Molecule Libraries/chemistry , Antitubercular Agents/chemical synthesis , Bacterial Proteins/chemistry , Crystallography, X-Ray , Enzyme Inhibitors/chemical synthesis , Ligands , Models, Molecular , Molecular Structure , Oxidoreductases/chemistry , Small Molecule Libraries/chemical synthesis , Surface Plasmon Resonance
7.
Eur J Med Chem ; 145: 539-550, 2018 Feb 10.
Article in English | MEDLINE | ID: mdl-29335214

ABSTRACT

BM635 is the hit compound of a promising anti-TB compound class. Herein we report systematic variations around the central pyrrole core of BM635 and we describe the design, synthesis, biological evaluation, pharmacokinetic analysis, as well as in vivo TB mouse efficacy studies of novel BM635 analogues that show improved physicochemical properties. This hit-to-lead campaign led to the identification of a new analogue, 4-((1-isopropyl-5-(4-isopropylphenyl)-2-methyl-1H-pyrrol-3-yl)methyl)morpholine (17), that shows excellent activity (MIC = 0.15 µM; SI = 133) against drug-sensitive Mycobacterium tuberculosis strains, as well as efficacy in a murine model of TB infection.


Subject(s)
Antitubercular Agents/pharmacology , Mycobacterium tuberculosis/drug effects , Pyrroles/pharmacology , Tuberculosis/drug therapy , Animals , Antitubercular Agents/chemical synthesis , Antitubercular Agents/chemistry , Cell Proliferation/drug effects , Cell Survival/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Design , Hep G2 Cells , Humans , Mice , Mice, Inbred C57BL , Microbial Sensitivity Tests , Molecular Structure , Pyrroles/chemical synthesis , Pyrroles/chemistry , Structure-Activity Relationship
8.
Eur J Pharm Sci ; 99: 17-23, 2017 Mar 01.
Article in English | MEDLINE | ID: mdl-27939618

ABSTRACT

BM635 is a small molecule endowed with outstanding anti-mycobacterial activity (minimum inhibitory concentration of 0.12µM against M. tuberculosis H37Rv) identified during a hit-to-lead campaign. Its poor aqueous solubility together with its high lipophilicity led to low exposure in vivo. Indeed, the half-life in vivo of BM635 was 1h, allowing a reasonable maximum concentration (Cmax=1.62µM) and a moderate bioavailability (46%). The present study aimed to develop salt forms of BM635 with pharmaceutically accepted hydrochloric, methanesulphonic, phosphoric, tartaric, and citric acids to overcome these drawbacks. BM635 salts (BM635-HCl, BM635-Mes, BM635-PA, BM635-TA and BM635-CA) were evaluated for physicochemical as well as biopharmaceutical attributes.


Subject(s)
Anti-Bacterial Agents/chemistry , Salts/chemistry , Anti-Bacterial Agents/metabolism , Anti-Bacterial Agents/pharmacology , Biological Availability , Half-Life , Hydrogen-Ion Concentration , Mycobacterium tuberculosis/drug effects , Solubility , Water/chemistry
9.
EBioMedicine ; 8: 291-301, 2016 Jun.
Article in English | MEDLINE | ID: mdl-27428438

ABSTRACT

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-Resistant
10.
J Med Chem ; 58(2): 613-24, 2015 Jan 22.
Article in English | MEDLINE | ID: mdl-25517015

ABSTRACT

Mycobacterial enoyl acyl carrier protein reductase (InhA) is a clinically validated target for the treatment of tuberculosis infections, a disease that still causes the death of at least a million people annually. A known class of potent, direct, and competitive InhA inhibitors based on a tetracyclic thiadiazole structure has been shown to have in vivo activity in murine models of tuberculosis infection. On the basis of this template, we have here explored the medicinal chemistry of truncated analogues that have only three aromatic rings. In particular, compounds 8b, 8d, 8f, 8l, and 8n show interesting features, including low nanomolar InhA IC50, submicromolar antimycobacterial potency, and improved physicochemical profiles in comparison with the tetracyclic analogues. From this series, 8d is identified as having the best balance of potency and properties, whereby the resolved 8d S-enatiomer shows encouraging in vivo efficacy.


Subject(s)
Antitubercular Agents/chemical synthesis , Bacterial Proteins/antagonists & inhibitors , Oxidoreductases/antagonists & inhibitors , Thiadiazoles/chemical synthesis , Animals , Antitubercular Agents/pharmacology , Bacterial Proteins/chemistry , Drug Design , Female , Hep G2 Cells , Humans , Mice , Mice, Inbred C57BL , Oxidoreductases/chemistry , Stereoisomerism , Structure-Activity Relationship , Thiadiazoles/pharmacology
SELECTION OF CITATIONS
SEARCH DETAIL
...