Supreeth Guptha
AstraZeneca
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Publication
Featured researches published by Supreeth Guptha.
Journal of Medicinal Chemistry | 2013
Manoj Kale; Anandkumar Raichurkar; Shahul Hameed P; David Waterson; David C. McKinney; M. R. Manjunatha; Usha Kranthi; Krishna Koushik; Lalit kumar Jena; Vikas Shinde; Suresh Rudrapatna; Shubhada Barde; Vaishali Humnabadkar; Prashanti Madhavapeddi; Halesha D. Basavarajappa; Anirban Ghosh; V. K. Ramya; Supreeth Guptha; Sreevalli Sharma; Prakash Vachaspati; K.N. Mahesh Kumar; Jayashree Giridhar; Jitendar Reddy; Samit Ganguly; Vijaykamal Ahuja; Sheshagiri Gaonkar; C. N. Naveen Kumar; Derek Ogg; Julie Tucker; P. Ann Boriack-Sjodin
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.
Bioorganic & Medicinal Chemistry Letters | 2013
Manoranjan Panda; Kakoli Mukherjee; Nilanjana Roy Choudhury; Subramanyam J. Tantry; Chaitanya Kumar Kedari; Sreevalli Sharma; V. K. Ramya; Supreeth Guptha; Vasan K. Sambandamurthy
Imidazo[1,2-a]pyridine-8-carboxamides as a novel antimycobacterial lead were generated by whole cell screening of a focused library against Mycobacterium tuberculosis. Herein, we describe the synthesis and structure activity relationship evaluation of this class of inhibitors and the optimization of physicochemical properties. These are selective inhibitors of Mycobacterium tuberculosis with no activity on either gram positive or gram negative pathogens.
Tuberculosis | 2015
Sudha Ravishankar; Anisha Ambady; Disha Awasthy; Naina Vinay Mudugal; Sreenivasaiah Menasinakai; Sandesh Jatheendranath; Supreeth Guptha; Sreevalli Sharma; Gayathri Balakrishnan; Radha Nandishaiah; Charles J. Eyermann; Folkert Reck; Suresh Rudrapatna; Vasan K. Sambandamurthy; Umender Sharma
DNA topoisomerases perform the essential function of maintaining DNA topology in prokaryotes. DNA gyrase, an essential enzyme that introduces negative supercoils, is a clinically validated target. However, topoisomerase I (Topo I), an enzyme responsible for DNA relaxation has received less attention as an antibacterial target, probably due to the ambiguity over its essentiality in many organisms. The Mycobacterium tuberculosis genome harbors a single topA gene with no obvious redundancy in its function suggesting an essential role. The topA gene could be inactivated only in the presence of a complementing copy of the gene in M. tuberculosis. Furthermore, down-regulation of topA in a genetically engineered strain of M. tuberculosis resulted in loss of bacterial viability which correlated with a concomitant depletion of intracellular Topo I levels. The topA knockdown strain of M. tuberculosis failed to establish infection in a murine model of TB and was cleared from lungs in two months post infection. Phenotypic screening of a Topo I overexpression strain led to the identification of an inhibitor, thereby providing chemical validation of this target. Thus, our work confirms the attractiveness of Topo I as an anti-mycobacterial target.
Journal of Medicinal Chemistry | 2014
Eknath Bellale; Maruti Naik; Varun Vb; Anisha Ambady; Ashwini Narayan; Sudha Ravishankar; Parvinder Kaur; Robert E. McLaughlin; James Whiteaker; Sapna Morayya; Supreeth Guptha; Sreevalli Sharma; Anandkumar Raichurkar; Disha Awasthy; Vijayshree Achar; Prakash Vachaspati; Balachandra Bandodkar; Manoranjan Panda; Monalisa Chatterji
Diarylthiazole (DAT), a hit from diversity screening, was found to have potent antimycobacterial activity against Mycobacterium tuberculosis (Mtb). In a systematic medicinal chemistry exploration, we demonstrated chemical opportunities to optimize the potency and physicochemical properties. The effort led to more than 10 compounds with submicromolar MICs and desirable physicochemical properties. The potent antimycobacterial activity, in conjunction with low molecular weight, made the series an attractive lead (antibacterial ligand efficiency (ALE)>0.4). The series exhibited excellent bactericidal activity and was active against drug-sensitive and resistant Mtb. Mutational analysis showed that mutations in prrB impart resistance to DAT compounds but not to reference drugs tested. The sensor kinase PrrB belongs to the PrrBA two component system and is potentially the target for DAT. PrrBA is a conserved, essential regulatory mechanism in Mtb and has been shown to have a role in virulence and metabolic adaptation to stress. Hence, DATs provide an opportunity to understand a completely new target system for antimycobacterial drug discovery.
ACS Medicinal Chemistry Letters | 2014
Maruti Naik; Sandeep R. Ghorpade; Lalit kumar Jena; Gopinath Gorai; Ashwini Narayan; Supreeth Guptha; Sreevalli Sharma; Neela Dinesh; Parvinder Kaur; Radha Nandishaiah; Jyothi Bhat; Gayathri Balakrishnan; Vaishali Humnabadkar; Lava Naviri; Pallavi Khadtare; Manoranjan Panda; Pravin S. Iyer; Monalisa Chatterji
A cellular activity-based screen on Mycobacterium tuberculosis (Mtb) H37Rv using a focused library from the AstraZeneca corporate collection led to the identification of 2-phenylindoles and arylsulphonamides, novel antimycobacterial scaffolds. Both the series were bactericidal in vitro and in an intracellular macrophage infection model, active against drug sensitive and drug resistant Mtb clinical isolates, and specific to mycobacteria. The scaffolds showed promising structure-activity relationships; compounds with submicromolar cellular potency were identified during the hit to lead exploration. Furthermore, compounds from both scaffolds were tested for inhibition of known target enzymes or pathways of antimycobacterial drugs including InhA, RNA polymerase, DprE1, topoisomerases, protein synthesis, and oxidative-phosphorylation. Compounds did not inhibit any of the targets suggesting the potential of a possible novel mode of action(s). Hence, both scaffolds provide the opportunity to be developed further as leads and tool compounds to uncover novel mechanisms for tuberculosis drug discovery.
Journal of Medicinal Chemistry | 2017
Subramanyam J. Tantry; Shankar D. Markad; Vikas Shinde; Jyothi Bhat; Gayathri Balakrishnan; Amit K. Gupta; Anisha Ambady; Anandkumar Raichurkar; Chaitanyakumar Kedari; Sreevalli Sharma; Naina V. Mudugal; Ashwini Narayan; C. N. Naveen Kumar; Robert Nanduri; Jitendar Reddy; K. R. Prabhakar; Karthikeyan Kandaswamy; Ramanatha Saralaya; Parvinder Kaur; Neela Dinesh; Supreeth Guptha; Kirsty Rich; David Murray; Helen Plant; Marian Preston; Helen Ashton; Darren Plant; Jarrod Walsh; Peter Alcock; Kathryn Naylor
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.
ACS Chemical Biology | 2014
Shahul Hameed P; Praveena Manjrekar; Murugan Chinnapattu; Vaishali Humnabadkar; Gajanan Shanbhag; Chaitanyakumar Kedari; Naina Vinay Mudugal; Anisha Ambady; Boudewijn L. M. de Jonge; Claire Sadler; Beena Paul; Shubha Sriram; Parvinder Kaur; Supreeth Guptha; Anandkumar Raichurkar; Paul R. Fleming; Charles J. Eyermann; David C. McKinney; Vasan K. Sambandamurthy; Manoranjan Panda; Sudha Ravishankar
The bacterial peptidoglycan biosynthesis pathway provides multiple targets for antibacterials, as proven by the clinical success of β-lactam and glycopeptide classes of antibiotics. The Mur ligases play an essential role in the biosynthesis of the peptidoglycan building block, N-acetyl-muramic acid-pentapeptide. MurC, the first of four Mur ligases, ligates l-alanine to UDP-N-acetylmuramic acid, initiating the synthesis of pentapeptide precursor. Therefore, inhibiting the MurC enzyme should result in bacterial cell death. Herein, we report a novel class of pyrazolopyrimidines with subnanomolar potency against both Escherichia coli and Pseudomonas aeruginosa MurC enzymes, which demonstrates a concomitant bactericidal activity against efflux-deficient strains. Radio-labeled precursor incorporation showed these compounds selectively inhibited peptidoglycan biosynthesis, and genetic studies confirmed the target of pyrazolopyrimidines to be MurC. In the presence of permeability enhancers such as colistin, pyrazolopyrimidines exhibited low micromolar MIC against the wild-type bacteria, thereby, indicating permeability and efflux as major challenges for this chemical series. Our studies provide biochemical and genetic evidence to support the essentiality of MurC and serve to validate the attractiveness of target for antibacterial discovery.
MedChemComm | 2016
Subramanyam J. Tantry; Vikas Shinde; Gayathri Balakrishnan; Shankar D. Markad; Amit K. Gupta; Jyothi Bhat; Ashwini Narayan; Anandkumar Raichurkar; Lalit kumar Jena; Sreevalli Sharma; Naveen Kumar; Robert Nanduri; Jitendar Reddy; K. R. Prabhakar; Karthikeyan Kandaswamy; Parvinder Kaur; Neela Dinesh; Supreeth Guptha; Ramanatha Saralaya; Manoranjan Panda; Suresh Rudrapatna; Meenakshi Mallya; Harvey Rubin; Takahiro Yano; Khisi Mdluili; Christopher B. Cooper; V. Balasubramanian; Vasan K. Sambandamurthy; Radha Shandil; Stefan Kavanagh
The success of bedaquiline as an anti-tubercular agent for the treatment of multidrug-resistant tuberculosis has validated the ATP synthesis pathway and in particular ATP synthase as an attractive target. However, limitations associated with its use in the clinic and the drug–drug interactions with rifampicin have prompted research efforts towards identifying alternative ATP synthesis inhibitors with differentiated mechanisms of action. A biochemical assay was employed to screen AstraZenecas corporate compound collection to identify the inhibitors of mycobacterial ATP synthesis. The high-throughput screening resulted in the identification of 2,4-diaminoquinazolines as inhibitors of the ATP synthesis pathway. A structure–activity relationship for the quinazolines was established and the knowledge was utilized to morph the quinazoline core into quinoline and pyrazolopyrimidine to expand the scope of chemical diversity. The morphed scaffolds exhibited a 10-fold improvement in enzyme potency and over 100-fold improvement in selectivity against inhibition of mammalian mitochondrial ATP synthesis. These novel compounds were bactericidal and demonstrated growth retardation of Mycobacterium tuberculosis in the acute mouse model of tuberculosis infection.
ChemMedChem | 2016
Sudhir Landge; Anupriya Kumar; João Neres; Kannan Murugan; Claire Sadler; Mick D. Fellows; Vaishali Humnabadkar; Prakash Vachaspati; Anandkumar Raichurkar; Sreevalli Sharma; Sudha Ravishankar; Supreeth Guptha; Vasan K. Sambandamurthy; Tanjore S. Balganesh; Bheemarao G. Ugarkar; V. Balasubramanian; Balachandra Bandodkar; Manoranjan Panda
Nitroarenes are less preferred in drug discovery due to their potential to be mutagenic. However, several nitroarenes were shown to be promising antitubercular agents with specific modes of action, namely, nitroimidazoles and benzothiazinones. The nitro group in these compounds is activated through different mechanisms, both enzymatic and non‐enzymatic, in mycobacteria prior to binding to the target of interest. From a whole‐cell screening program, we identified a novel lead nitrobenzothiazole (BT) series that acts by inhibition of decaprenylphosphoryl‐β‐d‐ribose 2′‐epimerase (DprE1) of Mycobacterium tuberculosis (Mtb). The lead was found to be mutagenic to start with. Our efforts to mitigate mutagenicity resulted in the identification of 6‐methyl‐7‐nitro‐5‐(trifluoromethyl)‐1,3‐benzothiazoles (cBTs), a novel class of antitubercular agents that are non‐mutagenic and exhibit an improved safety profile. The methyl group ortho to the nitro group decreases the electron affinity of the series, and is hence responsible for the non‐mutagenic nature of these compounds. Additionally, the co‐crystal structure of cBT in complex with Mtb DprE1 established the mode of binding. This investigation led to a new non‐mutagenic antitubercular agent and demonstrates that the mutagenic nature of nitroarenes can be solved by modulation of stereoelectronic properties.
PLOS ONE | 2016
Parvinder Kaur; Santanu Datta; Radha Shandil; Naveen Kumar; Nanduri Robert; Upneet K. Sokhi; Supreeth Guptha; Shridhar Narayanan; Anand Anbarasu; Sudha Ramaiah
One of the major impediments in anti-tubercular drug discovery is the lack of a robust grammar that governs the in-vitro to the in-vivo translation of efficacy. Mycobacterium tuberculosis (Mtb) is capable of growing both extracellular as well as intracellular; encountering various hostile conditions like acidic milieu, free radicals, starvation, oxygen deprivation, and immune effector mechanisms. Unique survival strategies of Mtb have prompted researchers to develop in-vitro equivalents to simulate in-vivo physiologies and exploited to find efficacious inhibitors against various phenotypes. Conventionally, the inhibitors are screened on Mtb under the conditions that are unrelated to the in-vivo disease environments. The present study was aimed to (1). Investigate cidality of Mtb targets using a non-chemical inhibitor antisense-RNA (AS-RNA) under in-vivo simulated in-vitro conditions.(2). Confirm the cidality of the targets under in-vivo in experimental tuberculosis. (3). Correlate in-vitro vs. in-vivo cidality data to identify the in-vitro condition that best predicts in-vivo cidality potential of the targets. Using cidality as a metric for efficacy, and AS-RNA as a target-specific inhibitor, we delineated the cidality potential of five target genes under six different physiological conditions (replicating, hypoxia, low pH, nutrient starvation, nitrogen depletion, and nitric oxide).In-vitro cidality confirmed in experimental tuberculosis in BALB/c mice using the AS-RNA allowed us to identify cidal targets in the rank order of rpoB>aroK>ppk>rpoC>ilvB. RpoB was used as the cidality control. In-vitro and in-vivo studies feature aroK (encoding shikimate kinase) as an in-vivo mycobactericidal target suitable for anti-TB drug discovery. In-vitro to in-vivo cidality correlations suggested the low pH (R = 0.9856) in-vitro model as best predictor of in-vivo cidality; however, similar correlation studies in pathologically relevant (Kramnik) mice are warranted. In the acute infection phase for the high fidelity translation, the compound efficacy may also be evaluated in the low pH, in addition to the standard replication condition.