Scaffold morphing leading to evolution of 2,4-diaminoquinolines and aminopyrazolopyrimidines as inhibitors of the ATP synthesis pathway

Tantry, Subramanyam J.; Shinde, Vikas; Balakrishnan, Gayathri; Markad, Shankar D.; Gupta, Amit K.; Bhat, Jyothi; Narayan, Ashwini; Raichurkar, Anandkumar; Jena, Lalit Kumar; Sharma, Sreevalli; Kumar, Naveen; Nanduri, Robert; Srinivasan, Bharath; Reddy, Jitendar; Panduga, Vijender; Prabhakar, K. R.; Kandaswamy, Karthikeyan; Kaur, Parvinder; Dinesh, Neela; Guptha, Supreeth; Saralaya, Ramanatha; Panda, Manoranjan; Rudrapatna, Suresh; Mallya, Meenakshi; Rubin, Harvey; Yano, Takahiro; Mdluili, Khisi; Cooper, Christopher B.; Balasubramanian, V.; Sambandamurthy, Vasan K.; Ramachandran, Vasanthi; Shandil, Radha; Kavanagh, Stefan; Narayanan, Shridhar; Iyer, Pravin S.; Mukherjee, Kakoli; Hosagrahara, Vinayak; Solapure, Suresh; P, Shahul Hameed; Ravishankar, Sudha

doi:10.1039/c5md00589b

Cited by 23 publications

(19 citation statements)

References 15 publications

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“…The growing interest in ATP synthase as a target and the emerging of BDQ resistance has resulted in a number of HTS and in silico screenings to identify additional options for ATP synthase inhibition and novel chemical entities for medicinal chemistry optimization, such as epigallocatechin [ 114 ], thiazolidones [ 115 ], and diaminoquinazolines [ 116 ].…”

Section: Classification Of Drugs Targeting Energy-metabolism In mentioning

confidence: 99%

SAR Analysis of Small Molecules Interfering with Energy-Metabolism in Mycobacterium tuberculosis

et al. 2020

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Tuberculosis remains the world’s top infectious killer: it caused a total of 1.5 million deaths and 10 million people fell ill with TB in 2018. Thanks to TB diagnosis and treatment, mortality has been falling in recent years, with an estimated 58 million saved lives between 2000 and 2018. However, the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mtb strains is a major concern that might reverse this progress. Therefore, the development of new drugs acting upon novel mechanisms of action is a high priority in the global health agenda. With the approval of bedaquiline, which targets mycobacterial energy production, and delamanid, which targets cell wall synthesis and energy production, the energy-metabolism in Mtb has received much attention in the last decade as a potential target to investigate and develop new antimycobacterial drugs. In this review, we describe potent anti-mycobacterial agents targeting the energy-metabolism at different steps with a special focus on structure-activity relationship (SAR) studies of the most advanced compound classes.

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Section: Classification Of Drugs Targeting Energy-metabolism In mentioning

confidence: 99%

SAR Analysis of Small Molecules Interfering with Energy-Metabolism in Mycobacterium tuberculosis

et al. 2020

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“…45 Bedaquiline demonstrates activity against both non-replicating and replicating mycobacteria, and against both drug-sensitive and drug resistant isolates. However, bedaquiline is subject to CYP3A4 metabolism, 46 and exhibits potent hERG channel inhibition, 47 and as such is subject to a limited indication of use in patients for which there is considerable unmet need and a positive benefit–risk balance.…”

Section: Identification Of Narrow-spectrum Antibacterial Agentsmentioning

confidence: 99%

“…20 In contrast, in Asia, South America, and the Middle East, it is the most dominant nosocomial organism responsible for infections. 45 The rise in the prevalence of A. baumannii infection, along with increasing drug-resistance has fostered an uptick in the development of both new A. baumannii small molecule interventions, and non-traditional approaches. Because A. baumannii has some unique biochemistry 78 and unique membrane 54 components when compared to other Gram-negative pathogens such as E. coli or P. aeruginosa , it may be more suited to the development of narrow-spectrum antibacterial agents.…”

Section: Identification Of Narrow-spectrum Antibacterial Agentsmentioning

confidence: 99%

Narrow-spectrum antibacterial agents

2018

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While broad spectrum antibiotics play an invaluable role in the treatment of bacterial infections, there are some drawbacks to their use, namely selection for and spread of resistance across multiple bacterial species, and the detrimental effect they can have upon the host microbiome. If the causitive agent of the infection is known, the use of narrow-spectrum antibacterial agents has the potential to mitigate some of these issues. This review outlines the advantages and challenges of narrow-spectrum antibacterial agents, discusses the progress that has been made toward developing diagnostics to enable their use, and describes some of the narrow-spectrum antibacterial agents currently being investigated against some of the most clinically important bacteria including Clostridium difficile, Mycobacterium tuberculosis and several ESKAPE pathogens.

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“…To achieve this we planned to build a homology model of pathogenic MTB rotor along with the subunit-a, so as to generate the interface which is known to host the binding site of bedaquiline. Previous workers performed molecular docking studies employing homology model of ac12 protein complex using E. coli F1F0 ATP synthase subunit-a and rotor complex (PDB ID: 1C17) as template that share relatively low sequence similarity (Table-1) [16][17][18][19]. One advantage with 1C17 template, despite low sequence identity with query sequence is presence of both subunit-a and entire rotor with c12 configuration.…”

Section: Methodsmentioning

confidence: 99%

in silico Quest Guided by Physico-Chemical Descriptors of Bedaquiline for New Scaffolds with Potential Inhibitory Capacity against Homology Model of Mycobacterium F1F0 ATP Synthase

Munnaluri¹,

Manga²

2018

Asian J. Chem.

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As the first US FDA approved drug for treating pulmonary multi drug resistant tuberculosis (MDR-TB) in the last 40 years, bedaquiline (TMC207, Sirturo TM ) stands out as cynosure in the circles of synthetic chemists exploring new therapeutics against tuberculosis. The remarkable efficacy of bedaquiline in treating tuberuculosis lies in its ability to target the energy metabolism that affects both replicating as well as dormant forms of M. tuberculosis (MTB). Despite its promising antitubercular profile, bedaquiline raises serious concern with its string of side effects and emergence of resistant strains, warrants a quest for better substitutes. In the present work, we employed in silico methods like homology modeling and virtual screening to zero in on molecules that exhibit high affinity at the binding site of bedaquiline.

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Scaffold morphing leading to evolution of 2,4-diaminoquinolines and aminopyrazolopyrimidines as inhibitors of the ATP synthesis pathway

Abstract: 2,4-Diaminoquinazolines, 2,4-diaminoquinolines and aminopyrazolopyrimidines, inhibitors of mycobacterial ATP synthesis, are novel lead molecules towards discovery and development of new anti-tubercular agents.

Cited by 23 publications

References 15 publications

SAR Analysis of Small Molecules Interfering with Energy-Metabolism in Mycobacterium tuberculosis

SAR Analysis of Small Molecules Interfering with Energy-Metabolism in Mycobacterium tuberculosis

Narrow-spectrum antibacterial agents

in silico Quest Guided by Physico-Chemical Descriptors of Bedaquiline for New Scaffolds with Potential Inhibitory Capacity against Homology Model of Mycobacterium F1F0 ATP Synthase

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