Design and synthesis of an oral prodrug alalevonadifloxacin for the treatment of MRSA infection

Bhawsar, S. B.; Kale, Rajesh P.; Deshpande, P. K.; Yeole, Ravindra; Bhagwat, Sachin; Patel, Mahesh

doi:10.1016/j.bmcl.2021.128432

Cited by 10 publications

(4 citation statements)

References 12 publications

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“…However, 4 subjects enrolled in an intrapulmonary pharmacokinetics study following oral administration of alalevonadifloxacin (1000 mg twice daily for five days) to 30 healthy Indian adults reported mild cases of photophobia [ 283 ]. Alalevonadifloxacin (WCK 2349) is the prodrug of levonadifloxacin (the name of alalevonadifloxacin emerged from L -alanine ester of levonadifloxacin at the hydroxyl substituent of piperidine moiety) [ 306 ].…”

Section: Side-effects Of Fqs and Underlying Mechanismsmentioning

confidence: 99%

Overview of Side-Effects of Antibacterial Fluoroquinolones: New Drugs versus Old Drugs, a Step Forward in the Safety Profile?

Rusu

Arbănași

et al. 2023

Pharmaceutics

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Antibacterial fluoroquinolones (FQs) are frequently used in treating infections. However, the value of FQs is debatable due to their association with severe adverse effects (AEs). The Food and Drug Administration (FDA) issued safety warnings concerning their side-effects in 2008, followed by the European Medicine Agency (EMA) and regulatory authorities from other countries. Severe AEs associated with some FQs have been reported, leading to their withdrawal from the market. New systemic FQs have been recently approved. The FDA and EMA approved delafloxacin. Additionally, lascufloxacin, levonadifloxacin, nemonoxacin, sitafloxacin, and zabofloxacin were approved in their origin countries. The relevant AEs of FQs and their mechanisms of occurrence have been approached. New systemic FQs present potent antibacterial activity against many resistant bacteria (including resistance to FQs). Generally, in clinical studies, the new FQs were well-tolerated with mild or moderate AEs. All the new FQs approved in the origin countries require more clinical studies to meet FDA or EMA requirements. Post-marketing surveillance will confirm or infirm the known safety profile of these new antibacterial drugs. The main AEs of the FQs class were addressed, highlighting the existing data for the recently approved ones. In addition, the general management of AEs when they occur and the rational use and caution of modern FQs were outlined.

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Section: Side-effects Of Fqs and Underlying Mechanismsmentioning

confidence: 99%

Overview of Side-Effects of Antibacterial Fluoroquinolones: New Drugs versus Old Drugs, a Step Forward in the Safety Profile?

Rusu

Arbănași

et al. 2023

Pharmaceutics

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“…The compound exhibits very little phototoxicity and has high cardiovascular safety and prominent PK properties. Furthermore, antofloxacin could inhibit CYPIA2 activity, but only slight inhibition of CYP2D-6 was observed in a study of the effect of antofloxacin hydrochloride on cytochrome P450 (CYP450) isoforms in rats (with theophylline, midazolam, chlorzoxazone, dexmedetomidine, omeprazole, and diclofenac as probes in the self-control method) [ 49 ].…”

Section: Dna Topoisomerase Inhibitorsmentioning

confidence: 99%

A Comprehensive Overview of the Antibiotics Approved in the Last Two Decades: Retrospects and Prospects

et al. 2023

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Due to the overuse of antibiotics, bacterial resistance has markedly increased to become a global problem and a major threat to human health. Fortunately, in recent years, various new antibiotics have been developed through both improvements to traditional antibiotics and the discovery of antibiotics with novel mechanisms with the aim of addressing the decrease in the efficacy of traditional antibiotics. This manuscript reviews the antibiotics that have been approved for marketing in the last 20 years with an emphasis on the antibacterial properties, mechanisms, structure–activity relationships (SARs), and clinical safety of these antibiotics. Furthermore, the current deficiencies, opportunities for improvement, and prospects of antibiotics are thoroughly discussed to provide new insights for the design and development of safer and more potent antibiotics.

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“…An oral version with equal PK/PD was required as a step-down therapy and therefore the L-arginine salt formulation (alalevonadifloxacin or WCK 2349) was created. It has a high oral bioavailability (89%) and has been successfully developed and launched as levonadifloxacin oral prodrug formulation (EMROK O) in India [ 60 , 61 ]. Multiple phase I studies have been performed with levonadifloxacin IV and oral in India and the USA.…”

Section: Meeting the Unmet Need With Levonadifloxacin IV And Oralmentioning

confidence: 99%

Meeting the Unmet Need in the Management of MDR Gram-Positive Infections with Oral Bactericidal Agent Levonadifloxacin

Mehta

Mishra

Paliwal

et al. 2022

Critical Care Research and Practice

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Levonadifloxacin (intravenous) and its oral prodrug alalevonadifloxacin are broad-spectrum antibacterial agents developed for the treatment of difficult-to-treat infections caused by multidrug-resistant Gram-positive bacteria, especially methicillin-resistant Staphylococcus aureus, atypical bacteria, anaerobic bacteria, and biodefence pathogens as well as Gram-negative bacteria. Levonadifloxacin has a well-defined mechanism of action involving a strong affinity for DNA gyrase as well as topoisomerase IV. Alalevonadifloxacin with widely differing solubility and oral bioavailability has pharmacokinetic profile identical to levonadifloxacin. Unlike existing MRSA drugs such as vancomycin and linezolid, which cause unfavorable side effects like nephrotoxicity, bone-marrow toxicity, and muscle toxicity, levonadifloxacin/alalevonadifloxacin has demonstrated superior safety and tolerability features with no serious adverse events. Levonadifloxacin/alalevonadifloxacin could be a useful weapon in the battle against infections caused by resistant microorganisms and could be a preferred antibiotic of choice for empirical therapy in the future.

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Design and synthesis of an oral prodrug alalevonadifloxacin for the treatment of MRSA infection

Cited by 10 publications

References 12 publications

Overview of Side-Effects of Antibacterial Fluoroquinolones: New Drugs versus Old Drugs, a Step Forward in the Safety Profile?

Overview of Side-Effects of Antibacterial Fluoroquinolones: New Drugs versus Old Drugs, a Step Forward in the Safety Profile?

A Comprehensive Overview of the Antibiotics Approved in the Last Two Decades: Retrospects and Prospects

Meeting the Unmet Need in the Management of MDR Gram-Positive Infections with Oral Bactericidal Agent Levonadifloxacin

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