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1.
J Med Chem ; 64(23): 17004-17030, 2021 12 09.
Article in English | MEDLINE | ID: mdl-34843241

ABSTRACT

The role of calcium release-activated calcium (CRAC) channels is well characterized and is of particular importance in T-cell function. CRAC channels are involved in the pathogenesis of several autoimmune diseases, making it an attractive therapeutic target for treating inflammatory diseases, like rheumatoid arthritis (RA). A systematic structure-activity relationship study with the goal of optimizing lipophilicity successfully yielded two lead compounds, 36 and 37. Both compounds showed decent potency and selectivity and a remarkable pharmacokinetic profile. Further characterization in in vivo RA models and subsequent histopathological evaluation of tissues led to the identification of 36 as a clinical candidate. Compound 36 displayed an excellent safety profile and had a sufficient safety margin to qualify it for use in human testing. Oral administration of 36 in Phase 1 clinical study in healthy volunteers established favorable safety, tolerability, and good target engagement as measured by levels of IL-2 and TNF-α.


Subject(s)
Calcium Channel Blockers/pharmacology , Calcium Release Activated Calcium Channels/antagonists & inhibitors , Calcium/metabolism , Drug Discovery , Administration, Oral , Animals , Area Under Curve , Arthritis, Rheumatoid/drug therapy , Calcium Channel Blockers/pharmacokinetics , Clinical Trials, Phase I as Topic , Humans , Jurkat Cells , Male , Mice , Mice, Inbred BALB C , Rats , Rats, Inbred Lew , Structure-Activity Relationship
2.
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
3.
Indian J Microbiol ; 56(1): 99-102, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26843702

ABSTRACT

A new fungal pathogen was isolated from rotten pomegranates collected from the orchards of different parts of Maharashtra. The pathogen was morphologically identified as Chaetomella raphigera followed by sequencing of ITS and D1/D2 hypervariable region of LSU (28S) of rRNA gene. The pathogen produced pectinase, cellulase, xylanase and protease in liquid medium at a concentration of 71, 13.8, 54.3 and 7 U/ml respectively. Enzyme activity was also determined during pathogenesis in the tissues artificially infected by C. raphigera. Xylanase activity was maximum (25.1 U/g) followed by pectinase (19.2 U/g) and cellulase (1.5 U/g), whereas, protease activity was unnoticed. There was significant correlation (P < 0.05) between disease rating scale and pectinase, xylanase and cellulase activity in infected tissues. This indicates the simultaneous production of hydrolytic enzymes that aids in necrosis of fruit tissues. The elevated levels of these enzymes in infected tissues as compared with control suggest their possible role in pathogenesis. Thus, pectinase, cellulase and xylanase produced by C. raphigera acts as major virulence factors in the development of fruit rot in pomegranates. This is a first report of fungal fruit rot caused by C. raphigera in pomegranate.

4.
ACS Med Chem Lett ; 6(7): 741-6, 2015 Jul 09.
Article in English | MEDLINE | ID: mdl-26191359

ABSTRACT

Structure-activity relationship (SAR) exploration on the left-hand side (LHS) of a novel class of bacterial topoisomerase inhibitors led to a significant improvement in the selectivity against hERG cardiac channel binding with concomitant potent antimycobacterial activity. Bulky polar substituents at the C-7 position of the naphthyridone ring did not disturb its positioning between two base pairs of DNA. Further optimization of the polar substituents on the LHS of the naphthyridone ring led to potent antimycobacterial activity (Mtb MIC = 0.06 µM) against Mycobacterium tuberculosis (Mtb). Additionally, this knowledge provided a robust SAR understanding to mitigate the hERG risk. This compound class inhibits Mtb DNA gyrase and retains its antimycobacterial activity against moxifloxacin-resistant strains of Mtb. Finally, we demonstrate in vivo proof of concept in an acute mouse model of TB following oral administration of compound 19.

5.
J Med Chem ; 57(11): 4889-905, 2014 Jun 12.
Article in English | MEDLINE | ID: mdl-24809953

ABSTRACT

DNA gyrase is a clinically validated target for developing drugs against Mycobacterium tuberculosis (Mtb). Despite the promise of fluoroquinolones (FQs) as anti-tuberculosis drugs, the prevalence of pre-existing resistance to FQs is likely to restrict their clinical value. We describe a novel class of N-linked aminopiperidinyl alkyl quinolones and naphthyridones that kills Mtb by inhibiting the DNA gyrase activity. The mechanism of inhibition of DNA gyrase was distinct from the fluoroquinolones, as shown by their ability to inhibit the growth of fluoroquinolone-resistant Mtb. Biochemical studies demonstrated this class to exert its action via single-strand cleavage rather than double-strand cleavage, as seen with fluoroquinolones. The compounds are highly bactericidal against extracellular as well as intracellular Mtb. Lead optimization resulted in the identification of potent compounds with improved oral bioavailability and reduced cardiac ion channel liability. Compounds from this series are efficacious in various murine models of tuberculosis.


Subject(s)
Antitubercular Agents/chemical synthesis , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Mycobacterium tuberculosis/drug effects , Piperidines/chemical synthesis , Topoisomerase II Inhibitors/chemical synthesis , Acute Disease , Administration, Oral , Animals , Antitubercular Agents/pharmacokinetics , Antitubercular Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Biological Availability , Chronic Disease , DNA Gyrase/genetics , DNA Gyrase/metabolism , Drug Resistance, Bacterial , ERG1 Potassium Channel , Fluoroquinolones/pharmacology , Humans , Macrophages/drug effects , Macrophages/microbiology , Mice, Inbred BALB C , Microbial Sensitivity Tests , Molecular Docking Simulation , Mutation , Mycobacterium tuberculosis/enzymology , Piperidines/pharmacokinetics , Piperidines/pharmacology , Protein Subunits/genetics , Protein Subunits/metabolism , Rats , Stereoisomerism , Structure-Activity Relationship , Topoisomerase II Inhibitors/pharmacokinetics , Topoisomerase II Inhibitors/pharmacology , Tuberculosis, Pulmonary/drug therapy
6.
Antimicrob Agents Chemother ; 58(6): 3312-26, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24687493

ABSTRACT

Pantothenate kinase (PanK) catalyzes the phosphorylation of pantothenate, the first committed and rate-limiting step toward coenzyme A (CoA) biosynthesis. In our earlier reports, we had established that the type I isoform encoded by the coaA gene is an essential pantothenate kinase in Mycobacterium tuberculosis, and this vital information was then exploited to screen large libraries for identification of mechanistically different classes of PanK inhibitors. The present report summarizes the synthesis and expansion efforts to understand the structure-activity relationships leading to the optimization of enzyme inhibition along with antimycobacterial activity. Additionally, we report the progression of two distinct classes of inhibitors, the triazoles, which are ATP competitors, and the biaryl acetic acids, with a mixed mode of inhibition. Cocrystallization studies provided evidence of these inhibitors binding to the enzyme. This was further substantiated with the biaryl acids having MIC against the wild-type M. tuberculosis strain and the subsequent establishment of a target link with an upshift in MIC in a strain overexpressing PanK. On the other hand, the ATP competitors had cellular activity only in a M. tuberculosis knockdown strain with reduced PanK expression levels. Additionally, in vitro and in vivo survival kinetic studies performed with a M. tuberculosis PanK (MtPanK) knockdown strain indicated that the target levels have to be significantly reduced to bring in growth inhibition. The dual approaches employed here thus established the poor vulnerability of PanK in M. tuberculosis.


Subject(s)
Antitubercular Agents/pharmacology , Enzyme Inhibitors/pharmacology , Mycobacterium tuberculosis/drug effects , Mycobacterium tuberculosis/enzymology , Phosphotransferases (Alcohol Group Acceptor)/antagonists & inhibitors , Blotting, Western , Gene Knockdown Techniques , Humans , Microbial Sensitivity Tests , Mycobacterium bovis/genetics , Mycobacterium tuberculosis/genetics , Phenotype , Phosphorylation , Phosphotransferases (Alcohol Group Acceptor)/genetics , Protein Conformation , Quinolones/pharmacology , Structure-Activity Relationship , Triazoles/pharmacology
7.
Bioorg Med Chem Lett ; 24(3): 870-9, 2014 Feb 01.
Article in English | MEDLINE | ID: mdl-24405701

ABSTRACT

Scaffold hopping from the thiazolopyridine ureas led to thiazolopyridone ureas with potent antitubercular activity acting through inhibition of DNA GyrB ATPase activity. Structural diversity was introduced, by extension of substituents from the thiazolopyridone N-4 position, to access hydrophobic interactions in the ribose pocket of the ATP binding region of GyrB. Further optimization of hydrogen bond interactions with arginines in site-2 of GyrB active site pocket led to potent inhibition of the enzyme (IC50 2 nM) along with potent cellular activity (MIC=0.1 µM) against Mycobacterium tuberculosis (Mtb). Efficacy was demonstrated in an acute mouse model of tuberculosis on oral administration.


Subject(s)
Mycobacterium tuberculosis/drug effects , Pyridones/chemical synthesis , Thiazoles/chemical synthesis , Topoisomerase II Inhibitors/chemical synthesis , Topoisomerase II Inhibitors/pharmacology , Urea/chemical synthesis , Urea/pharmacology , Administration, Oral , Animals , Antitubercular Agents/chemical synthesis , Antitubercular Agents/chemistry , Antitubercular Agents/pharmacology , Disease Models, Animal , Inhibitory Concentration 50 , Mice , Microbial Sensitivity Tests , Molecular Structure , Pyridones/chemistry , Pyridones/pharmacology , Thiazoles/chemistry , Thiazoles/pharmacology , Topoisomerase II Inhibitors/chemistry , Urea/chemistry
8.
J Med Chem ; 56(23): 9701-8, 2013 Dec 12.
Article in English | MEDLINE | ID: mdl-24215368

ABSTRACT

We report 1,4-azaindoles as a new inhibitor class that kills Mycobacterium tuberculosis in vitro and demonstrates efficacy in mouse tuberculosis models. The series emerged from scaffold morphing efforts and was demonstrated to noncovalently inhibit decaprenylphosphoryl-ß-D-ribose2'-epimerase (DprE1). With "drug-like" properties and no expectation of pre-existing resistance in the clinic, this chemical class has the potential to be developed as a therapy for drug-sensitive and drug-resistant tuberculosis.


Subject(s)
Antitubercular Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Indoles/chemical synthesis , Mycobacterium tuberculosis/drug effects , Oxidoreductases/antagonists & inhibitors , Alcohol Oxidoreductases , Animals , Antitubercular Agents/pharmacokinetics , Antitubercular Agents/therapeutic use , Drug Discovery , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Indoles/pharmacokinetics , Indoles/pharmacology , Indoles/therapeutic use , Mice , Rats , Tuberculosis, Multidrug-Resistant/drug therapy
9.
J Med Chem ; 56(21): 8533-42, 2013 Nov 14.
Article in English | MEDLINE | ID: mdl-24107081

ABSTRACT

InhA is a well validated Mycobacterium tuberculosis (Mtb) target as evidenced by the clinical success of isoniazid. Translating enzyme inhibition to bacterial cidality by targeting the fatty acid substrate site of InhA remains a daunting challenge. The recent disclosure of a methyl-thiazole series demonstrates that bacterial cidality can be achieved with potent enzyme inhibition and appropriate physicochemical properties. In this study, we report the molecular mode of action of a lead methyl-thiazole, along with analogues with improved CYP inhibition profile. We have identified a novel mechanism of InhA inhibition characterized by a hitherto unreported "Y158-out" inhibitor-bound conformation of the protein that accommodates a neutrally charged "warhead". An additional novel hydrophilic interaction with protein residue M98 allows the incorporation of favorable physicochemical properties for cellular activity. Notably, the methyl-thiazole prefers the NADH-bound form of the enzyme with a Kd of ~13.7 nM, as against the NAD(+)-bound form of the enzyme.


Subject(s)
Bacterial Proteins/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Mycobacterium tuberculosis/enzymology , Oxidoreductases/antagonists & inhibitors , Thiazoles/pharmacology , Bacterial Proteins/metabolism , Crystallography, X-Ray , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Models, Molecular , Molecular Structure , Oxidoreductases/metabolism , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/chemistry
10.
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
12.
J Pharm Biomed Anal ; 43(1): 381-6, 2007 Jan 04.
Article in English | MEDLINE | ID: mdl-16926080

ABSTRACT

LC-UV scan of lisinopril revealed the presence of an unknown impurity (approximately 0.14%) at a relative retention time of 3.26 employing phosphate buffer-acetonitrile as binary gradient system while LC-MS analysis with binary gradient system comprising of a ammonia-ammonium acetate buffer (pH 5.0) and acetonitrile indicated it to be C31H41N3O7. The impurity was isolated by preparative HPLC utilizing a linear gradient of water and acetonitrile. The structural analysis of the isolated product by 1H, 13C NMR, mass spectroscopy and FT-IR revealed it to be a 4-phenyl butanoic acid derivative (CL) of lisinopril.


Subject(s)
Lisinopril/analysis , Ammonia/chemistry , Chromatography, High Pressure Liquid , Drug Contamination , Gas Chromatography-Mass Spectrometry , Magnetic Resonance Spectroscopy , Mass Spectrometry , Solutions , Spectrophotometry, Ultraviolet , Spectroscopy, Fourier Transform Infrared
13.
J Pharm Biomed Anal ; 42(3): 395-9, 2006 Sep 26.
Article in English | MEDLINE | ID: mdl-16765551

ABSTRACT

The presence of unknown impurity of the order of 0.2% was identified in benazepril using liquid chromatographic technique employing binary gradient system comprising acetic acid and ammonia in water and acetonitrile as the mobile phase. LCMS data corresponds to hydroxylated benazepril (OHB) derivative possessing the molecular formula C(24)H(28)N(2)O(6). This impurity was isolated using isocratic system containing ammonium acetate and acetonitrile and the product was characterized using FT-IR, (1)H and (13)C NMR and mass spectroscopy to ascertain the structure of the impurity. The spectroscopic analysis revealed the presence of hydroxyl function on C(17) carbon atom of benazepril molecule. The plausible mechanism for the formation of OHB species is proposed.


Subject(s)
Benzazepines/analysis , Drug Contamination , Chromatography, Liquid , Magnetic Resonance Spectroscopy , Mass Spectrometry , Spectroscopy, Fourier Transform Infrared
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