A5027978440- Tuberculosis Research and Epidemiology
- Malaria Research and Control
- Mosquito-borne diseases and control
- Cancer therapeutics and mechanisms
- Trypanosoma species research and implications
- Research on Leishmaniasis Studies
- HIV Research and Treatment
- Biochemical and Molecular Research
- Quinazolinone synthesis and applications
- Mycobacterium research and diagnosis
- HIV/AIDS drug development and treatment
- Phenothiazines and Benzothiazines Synthesis and Activities
- Computational Drug Discovery Methods
- Drug Transport and Resistance Mechanisms
- Synthesis and Biological Evaluation
- Viral Infections and Vectors
- Pharmacogenetics and Drug Metabolism
- Drug-Induced Hepatotoxicity and Protection
- X-ray Diffraction in Crystallography
- Synthesis and biological activity
- Antibiotics Pharmacokinetics and Efficacy
- Amoebic Infections and Treatments
- Parasitic Infections and Diagnostics
- Crystallization and Solubility Studies
- Clostridium difficile and Clostridium perfringens research
Novartis (Switzerland)
2010-2025
Novartis (United States)
2011-2024
Novartis (Singapore)
2010-2023
Swiss Tropical and Public Health Institute
2010-2020
University of Basel
2010-2020
University of Bern
2020
Johns Hopkins University
2020
National University Health System
2014
National University of Singapore
2014
Genomics Institute of the Novartis Research Foundation
2010-2011
Recent reports of increased tolerance to artemisinin derivatives--the most recently adopted class antimalarials--have prompted a need for new treatments. The spirotetrahydro-beta-carbolines, or spiroindolones, are potent drugs that kill the blood stages Plasmodium falciparum and vivax clinical isolates at low nanomolar concentration. Spiroindolones rapidly inhibit protein synthesis in P. falciparum, an effect is ablated parasites bearing nonsynonymous mutations gene encoding P-type...
The antiplasmodial activity of a series spirotetrahydro β-carbolines is described. Racemic spiroazepineindole (1) was identified from phenotypic screen on wild type Plasmodium falciparum with an in vitro IC50 90 nM. Structure−activity relationships for the optimization 1 to compound 20a (IC50 = 0.2 nM) including identification active 1R,3S enantiomer and elimination metabolic liabilities presented. Improvement pharmacokinetic profile translated exceptional oral efficacy P. berghei infected...
Dengue virus (DENV), a mosquito-borne flavivirus, is major public health threat. The poses risk to 2.5 billion people worldwide and causes 50 100 million human infections each year. Neither vaccine nor an antiviral therapy currently available for prevention treatment of DENV infection. Here, we report previously undescribed adenosine analog, NITD008, that potently inhibits both in vitro vivo. In addition the 4 serotypes DENV, NITD008 other flaviviruses, including West Nile virus, yellow...
Candidate antibacterials are usually identified on the basis of their in vitro activity. However, apparent inhibitory activity new leads can be misleading because most culture media do not reproduce an environment relevant to infection vivo. In this study, while screening for novel anti-tuberculars, we uncovered how carbon metabolism affect antimicrobial Novel pyrimidine-imidazoles (PIs) were a whole-cell screen against Mycobacterium tuberculosis. Lead optimization generated potent...
Abstract Objectives The discovery and development of TB drugs has met limited success, with two new approved over the last 40 years. Part difficulty resides in lack well-established vitro or vivo targets potency physicochemical pharmacokinetic parameters. In an attempt to benchmark compare such properties for anti-TB agents, we have experimentally determined compiled these parameters 36 compounds, using standardized centralized assays, thus ensuring direct comparability across drug classes....
New chemotherapeutic compounds against multidrug-resistant Mycobacterium tuberculosis (Mtb) are urgently needed to combat drug resistance in (TB). We have identified and characterized the indolcarboxamides as a new class of antitubercular bactericidal agent. Genetic lipid profiling studies likely molecular target MmpL3, transporter trehalose monomycolate that is essential for mycobacterial cell wall biosynthesis. Two lead candidates, NITD-304 NITD-349, showed potent activity both...
Alleviating the burden of tuberculosis (TB) requires an understanding genetic basis that determines emergence drug-resistant mutants. PA-824 (pretomanid) is a bicyclic nitroimidazole class compound presently undergoing phase III STAND clinical trial, despite lacking identifiable markers for drug-specific resistant Mycobacterium tuberculosis. In present study, we aimed to characterize polymorphisms spontaneously generated PA-824-resistant mutant strains by surveying drug metabolism genes...
4-Hydroxy-2-pyridones, direct inhibitors of the mycobacterial protein InhA, are active against multidrug-resistant Mycobacterium tuberculosis .
The four serotypes of dengue virus (DENV-1 to -4) represent the most prevalent mosquito-borne viral pathogens in humans. No clinically approved vaccine or antiviral is currently available for DENV. Here we report a spiropyrazolopyridone compound that potently inhibits DENV both vitro and vivo. inhibitor was identified through screening 1.8-million-compound library by using DENV-2 replicon assay. selectively -3 (50% effective concentration [EC50], 10 80 nM) but not DENV-1 -4 (EC50,>20 M)....
Dengue virus (DENV) is a mosquito-borne flavivirus that poses threat to public health, yet no antiviral drug available. We performed high-throughput phenotypic screen using the Novartis compound library and identified candidate chemical inhibitors of DENV. This series was optimized improve properties such as anti-DENV potency solubility. The lead compound, NITD-688, showed strong against all four serotypes DENV demonstrated excellent oral efficacy in infected AG129 mice. There 1.44-log...
Millions who live in Latin America and sub-Saharan Africa are at risk of trypanosomatid infections, which cause Chagas disease human African trypanosomiasis (HAT). Improved HAT treatments available, but therapies rely on two nitroheterocycles, suffer from lengthy drug regimens safety concerns that frequent treatment discontinuation. We performed phenotypic screening against trypanosomes identified a class cyanotriazoles (CTs) with potent trypanocidal activity both vitro mouse models HAT....
Starting from a hit series GNF compound library collection and based on cell-based proliferation assay of Plasmodium falciparum, novel imidazolopiperazine scaffold was optimized. SAR for this compounds is discussed, focusing optimization cellular potency against wild-type drug resistant parasites improvement physiochemical pharmacokinetic properties. The lead in showed good potencies vitro decent oral exposure levels vivo. In berghei mouse infection model, one lowered the parasitemia level...
Indole-2-carboxamides have been identified as a promising class of antituberculosis agents from phenotypic screening against mycobacteria. One the hits, indole-2-carboxamide analog (1), had low micromolar potency Mycobacterium tuberculosis (Mtb), high mouse liver microsomal clearance, and aqueous solubility. Structure–activity relationship studies revealed that attaching alkyl groups to cyclohexyl ring significantly improved Mtb activity but reduced Furthermore, chloro, fluoro, or cyano...
On the basis of initial success optimization a novel series imidazolopiperazines, second generation compounds involving changes in core piperazine ring was synthesized to improve antimalarial properties. These were carried out further potency and metabolic stability by leveraging outcome set vitro identification studies. The optimized 8,8-dimethyl imidazolopiperazine analogues exhibited improved potency, profile and, as result, enhanced oral exposure vivo mice. found be more efficacious than...
Two Plasmodium PI4 kinase (PI4K) inhibitors, KDU691 and LMV599, were selected for in vivo testing as causal prophylactic radical-cure agents cynomolgi sporozoite-infected rhesus macaques, based on their vitro activity against liver stages. Animals infected with P. sporozoites, compounds dosed orally. Both the LMV599 fully protective when administered prophylactically, more potent compound achieved protection a single oral dose of 25 mg/kg body weight. In contrast, tested radical cure, five...
A series of 5-aryl-2-amino-imidazothiadiazole (ITD) derivatives were identified by a phenotype-based high-throughput screening using blood stage Plasmodium falciparum (Pf) growth inhibition assay. lead optimization program focused on improving antiplasmodium potency, selectivity against human kinases, and absorption, distribution, metabolism, excretion, toxicity properties extended pharmacological profiles culminated in the identification INE963 (1), which demonstrates potent cellular...
Diarrhoeal disease caused by Cryptosporidium is a major cause of morbidity and mortality in young malnourished children from low- middle-income countries, with no vaccine or effective treatment. Here we describe the discovery EDI048, PI(4)K inhibitor, designed to be active at infection site gastrointestinal tract undergo rapid metabolism liver. By using mutational analysis crystal structure, show that EDI048 binds highly conserved amino acid residues ATP-binding site. orally efficacious an...
ABSTRACT Cardiomyopathy is the most common pathology associated with Trypanosoma cruzi infection. Reports that statins have both cardioprotective and trypanocidal activity generated interest in their potential as a therapeutic treatment. Using highly-sensitive bioluminescent mouse model, we show 5 days treatment has no significant impact on parasite load. The free systemic concentrations fail to reach level required for potency. Hence, clinical trials investigate of lack experimental justification.
Dengue virus (DENV) is the most prevalent mosquito-borne viral pathogen that infects humans. Neither a vaccine nor an antiviral therapy currently available for DENV. Here, we report adenosine nucleoside prodrug potently inhibits DENV replication both in cell culture and mouse model. NITD449 (2'-C-acetylene-7-deaza-7-carbamoyladenosine) was initially identified as parental compound all four serotypes of with low cytotoxicity. However, vivo pharmacokinetic studies indicated had level exposure...
ABSTRACT We describe a novel translation inhibitor that has anti-dengue virus (DENV) activity in vitro and vivo . The was identified through high-throughput screening using DENV infection assay. compound contains benzomorphan core structure. Mode-of-action analysis indicated the inhibits protein viral RNA sequence-independent manner. Analysis of stereochemistry demonstrated only one enantiomer racemic translation. Medicinal chemistry performed to eliminate metabolically labile...
Tetrahydropyrazolo[1,5-a]pyrimidine scaffold was identified as a hit series from Mycobacterium tuberculosis (Mtb) whole cell high through-put screening (HTS) campaign. A of derivatives this class were synthesized to evaluate their structure–activity relationship (SAR) and structure–property (SPR). Compound 9 had promising in vivo DMPK profile mouse exhibited potent activity efficacy model, achieving reduction 3.5 log CFU Mtb after oral administration infected mice once day at 100 mg/kg for...
The (S)-2-nitro-6-(4-(trifluoromethoxy)benzyloxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine named PA-824 (1) has demonstrated antitubercular activity in vitro and animal models is currently clinical trials. We synthesized derivatives at three positions of the 4-(trifluoromethoxy)benzylamino tail, these were tested for whole-cell against both replicating nonreplicating Mycobacterium tuberculosis (Mtb). In addition, we determined their kinetic parameters as substrates deazaflavin-dependent...