A5010023715- Tuberculosis Research and Epidemiology
- Cancer therapeutics and mechanisms
- Biochemical and Molecular Research
- Malaria Research and Control
- Bacteriophages and microbial interactions
- Bacterial Genetics and Biotechnology
- HIV/AIDS drug development and treatment
- Antibiotic Resistance in Bacteria
- Pneumocystis jirovecii pneumonia detection and treatment
- Mycobacterium research and diagnosis
- Phenothiazines and Benzothiazines Synthesis and Activities
- Trypanosoma species research and implications
- ATP Synthase and ATPases Research
- Antibiotics Pharmacokinetics and Efficacy
- RNA and protein synthesis mechanisms
- HIV Research and Treatment
- Drug Transport and Resistance Mechanisms
- Synthesis and biological activity
- vaccines and immunoinformatics approaches
- Enzyme Catalysis and Immobilization
- Research on Leishmaniasis Studies
- Peptidase Inhibition and Analysis
- Glycosylation and Glycoproteins Research
- Diet, Metabolism, and Disease
- Pancreatic function and diabetes
Acharya Nagarjuna University
2017-2018
AstraZeneca (India)
2005-2017
AstraZeneca (United Kingdom)
2011-2013
MMV390048, a member of new class inhibitors the Plasmodium phosphatidylinositol 4-kinase, shows potential for both treatment and prophylaxis.
We report 1,4-azaindoles as a new inhibitor class that kills Mycobacterium tuberculosis in vitro and demonstrates efficacy mouse models. The series emerged from scaffold morphing efforts was demonstrated to noncovalently inhibit decaprenylphosphoryl-β-D-ribose2'-epimerase (DprE1). With "drug-like" properties no expectation of pre-existing resistance the clinic, this chemical has potential be developed therapy for drug-sensitive drug-resistant tuberculosis.
The 2-aminopyridine MMV048 was the first drug candidate inhibiting Plasmodium phosphatidylinositol 4-kinase (PI4K), a novel target for malaria, to enter clinical development. In an effort identify next generation of PI4K inhibitors, series optimized improve properties such as solubility and antiplasmodial potency across parasite life cycle, leading 2-aminopyrazine UCT943.
The approval of bedaquiline to treat tuberculosis has validated adenosine triphosphate (ATP) synthase as an attractive target kill Mycobacterium (Mtb). Herein, we report the discovery two diverse lead series imidazo[1,2-a]pyridine ethers (IPE) and squaramides (SQA) inhibitors mycobacterial ATP synthesis. Through medicinal chemistry exploration, established a robust structure-activity relationship these scaffolds, resulting in nanomolar potencies synthesis inhibition assay. A biochemical...
New therapeutic strategies against multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis are urgently required to combat the global (TB) threat. Toward this end, we previously reported identification of 1,4-azaindoles, a promising class compounds with potent antitubercular activity through noncovalent inhibition decaprenylphosphoryl-β-D-ribose 2'-epimerase (DprE1). Further, series was optimized improve its physicochemical properties pharmacokinetics in...
Treatment of tuberculosis (TB) is impaired by the long duration and complexity therapy rising incidence drug resistance. There an urgent need for new agents with improved efficacy, safety, compatibility combination chemotherapies. Oxazolidinones offer a potential class TB drugs, linezolid-the only currently approved oxazolidinone-has proven highly effective against extensively drug-resistant (XDR) in experimental trials. However, widespread use linezolid prohibited its significant...
Beta-lactams, in combination with beta-lactamase inhibitors, are reported to have activity against Mycobacterium tuberculosis bacteria growing broth, as well inside the human macrophage. We tested representative beta-lactams belonging 3 different classes for replicating M. broth and nonreplicating under hypoxia, streptomycin-starved strain 18b (ss18b) presence or absence of clavulanate. Most combinations showed bactericidal tuberculosis, up 200-fold improvement potency None combinations,...
Abstract The widespread emergence of Plasmodium falciparum ( Pf ) strains resistant to frontline agents has fuelled the search for fast-acting with novel mechanism action. Here, we report discovery and optimization antimalarial compounds, triaminopyrimidines (TAPs), which emerged from a phenotypic screen against blood stages . clinical candidate (compound 12 is efficacious in mouse model malaria an ED 99 <30 mg kg −1 displays good vivo safety margins guinea pigs rats. With predicted...
DNA gyrase is a clinically validated target for developing drugs against Mycobacterium tuberculosis (Mtb). Despite the promise of fluoroquinolones (FQs) as anti-tuberculosis drugs, prevalence pre-existing resistance to FQs likely restrict their clinical value. We describe novel class N-linked aminopiperidinyl alkyl quinolones and naphthyridones that kills Mtb by inhibiting activity. The mechanism inhibition was distinct from fluoroquinolones, shown ability inhibit growth...
Moxifloxacin has shown excellent activity against drug-sensitive as well drug-resistant tuberculosis (TB), thus confirming DNA gyrase a clinically validated target for discovering novel anti-TB agents. We have identified inhibitors in the pyrrolamide class which kill Mycobacterium through inhibition of ATPase catalyzed by GyrB domain gyrase. A homology model M. H37Rv was used deciphering structure-activity relationship and binding interactions with mycobacterial enzyme. Proposed were later...
2,4-Diaminoquinazolines, 2,4-diaminoquinolines and aminopyrazolopyrimidines, inhibitors of mycobacterial ATP synthesis, are novel lead molecules towards discovery development new anti-tubercular agents.
Coadministration of moxifloxacin and rifampin was evaluated in a murine model Mycobacterium tuberculosis pulmonary infection to determine whether the finding antagonism documented hollow-fiber could be recapitulated vivo. Colony counts were followed no-treatment control group, groups administered or monotherapy, group combination two agents. Following 18 days once-daily oral administration mice infected with M. tuberculosis, there reduction plasma exposure that decreased further when...
The authors describe the discovery of anti-mycobacterial compounds through identifying mechanistically diverse inhibitors essential Mycobacterium tuberculosis (Mtb) enzyme, pantothenate kinase (CoaA). Target-driven drug technologies often work with purified enzymes, and thus discovered may not optimally inhibit form target enzyme predominant in bacterial cell or be available at desired concentration. Therefore, addition to addressing entry efflux issues, mechanisms inhibition (MoI) could...
Structure-activity relationship (SAR) exploration on the left-hand side (LHS) of a novel class bacterial topoisomerase inhibitors led to significant improvement in selectivity against hERG cardiac channel binding with concomitant potent antimycobacterial activity. Bulky polar substituents at C-7 position naphthyridone ring did not disturb its positioning between two base pairs DNA. Further optimization LHS activity (Mtb MIC = 0.06 μM) Mycobacterium tuberculosis (Mtb). Additionally, this...
ABSTRACT Class A high-molecular-weight penicillin-binding protein 1a (PBP1a) and PBP1b of Escherichia coli have both transglycosylase (TG) transpeptidase (TP) activity. These enzymes are difficult to assay, since their substrates prepare. We show the activity PBP1a or can be measured in membranes by cloning PBP into an E. ponB ::Spc r strain. Using this we that is ∼10-fold more sensitive penicillin than 50% inhibitory concentration (IC 50 ) moenomycin, a TG inhibitor, higher transformants...
RNA polymerase (RNAP) is a well-validated target for the development of antibacterial and antituberculosis agents. Because purification large quantities native from pathogenic mycobacteria hazardous cumbersome, primary screening was carried out using Escherichia coli RNAP. The authors have developed high-throughput (HTS) assay to screen novel inhibitors In this assay, fluorescent analog UTP, gamma-amino naphthalene sulfonic acid (gamma-AmNS) used as one nucleotide substrates. Incorporation...
MurG and MraY, essential enzymes involved in the synthesis of bacterial peptidoglycan, are difficult to assay because substrates lipidic hard prepare large quantities. Based on use Escherichia coli membranes lacking PBP1b, we report a high-throughput method measure activity and, optionally, MraY as well. In these membranes, incubation with two peptidoglycan sugar precursors results accumulation lipid II rather than produced by wild-type membranes. was assayed addition...
AZD5847, a novel oxazolidinone with an MIC of 1 μg/ml, exhibits exposure-dependent killing kinetics against extracellular and intracellular Mycobacterium tuberculosis. Oral administration AZD5847 to mice infected M. tuberculosis H37Rv in chronic-infection model resulted 1.0-log10 reduction the lung CFU count after 4 weeks treatment at daily area under concentration-time curve (AUC) 105 158 μg · h/ml. The pharmacokinetic-pharmacodynamic parameter that best predicted success acute-infection...
ABSTRACT There are currently 18 drug classes for the treatment of tuberculosis, including those in development pipeline. An silico simulation enabled combing innumerably large search space to derive multidrug combinations. Through use ordinary differential equations (ODE), we constructed an kinetic platform which major metabolic pathways Mycobacterium tuberculosis and mechanisms antituberculosis drugs were integrated into a virtual proteome. The optimized model was used evaluate 816 triplets...
MraY is an established target for the discovery of antibacterial agents.The conventional assay uses radioactive substrate and analysis products after paper chromatography or butanol extraction.Synthesis radiolabeled has been done in vitro using purified enzymes by growing cells on precursors.The authors report a simple rapid method to chemically radiolabel substrate, UDP-MurNAc-pentapeptide. Specific activity obtained this was more than 100 times higher conventionally labeled yields are high...
1. During the course of metabolic profiling lead Compound 1, glutathione (GSH) conjugates were detected in rat bile, suggesting formation reactive intermediate precursor(s). This was confirmed by identification GSH and N-acetylcysteine (NAC) microsomal incubations. 2. It proposed that bioactivation 1 occurs via a di-iminoquinone through involvement C-2 C-5 nitrogens pyrimidine core. 3. To further investigate this hypothesis, structural analogs with modifications at nitrogen studied for...