Conversion of <i>N-</i>acyl amidines to amidoximes: a convenient synthetic approach to molnupiravir (EIDD-2801) from ribose

Ahmed, Ajaz; Ahmed, Qazi Naveed; Mukherjee, Debaraj

doi:10.1039/d1ra06912h

Cited by 7 publications

(6 citation statements)

References 18 publications

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“…was synthesized, purified, and characterized using 1 H and 13 C nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HR-MS) (Figures S1−S3). 18 Chromatographic purity was determined by HPLC (Figure S4).…”

Section: Animal Modelmentioning

confidence: 99%

Impact of Disease States on the Oral Pharmacokinetics of EIDD-1931 (an Active Form of Molnupiravir) in Rats for Implication in the Dose Adjustment

Bhardwaj,

Gour,

Ahmed

et al. 2023

Mol. Pharmaceutics

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The pharmacokinetic alteration of an antimicrobial medication leading to sub-therapeutic plasma level can aid in the emergence of resistance, a global threat nowadays. In this context, molnupiravir (prodrug of EIDD-1931) is the most efficacious orally against corona virus disease (COVID-19). In addition to drug−drug interaction, the pharmacokinetics of a drug can significantly vary during any disease state, leading to disease−drug interaction. However, no information is available for such a recently approved drug. Therefore, we aimed to explore the oral pharmacokinetics of EIDD-1931 in seven chemically induced disease states individually compared to the normal state using various rat models. Induction of any disease situation was confirmed by the disease specific study(s) prior to pharmacokinetic investigations. Compared to the normal state, substantially lowered plasma exposure (0.47-and 0.63-fold) with notably enhanced clearance (2.00-and 1.56-fold) of EIDD-1931 was observed in rats of ethanol-induced gastric injury and carbon tetrachloride-induced liver injury states. Conversely, paclitaxel-induced neuropathic pain and cisplatin-induced kidney injury states exhibited opposite outcomes on oral exposure (1.43-and 1.50-fold) and clearance (0.69-and 0.65-fold) of EIDD-1931. Although the highest plasma concentration (2.26-fold) markedly augmented in the doxorubicin-induced cardiac injury state, streptozocin-induced diabetes and lipopolysaccharide-induced lung injury state did not substantially influence the pharmacokinetics of EIDD-1931. Exploring the possible phenomenon behind the reduced or boosted plasma exposure of EIDD-1931, results suggest the need for dose adjustment in respective diseased conditions in order to achieve desired efficacy during oral therapy of EIDD-1931.

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Section: Animal Modelmentioning

confidence: 99%

Impact of Disease States on the Oral Pharmacokinetics of EIDD-1931 (an Active Form of Molnupiravir) in Rats for Implication in the Dose Adjustment

Bhardwaj,

Gour,

Ahmed

et al. 2023

Mol. Pharmaceutics

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“…Molnupiravir (MK-4482, EIDD-2801) is an antiviral drug used to treat influenza virus. [45,46] Recently, it has also demonstrated activity against the coronavirus [47] due to which, a lot of research is being carried out to find the best suitable synthetic routes [48][49][50][51][52][53][54][55][56] to efficiently synthesize the drug and make it available for prompt clinical trials. Recently, Shen and coworkers [57] established a one-pot chemical synthetic route to access molnupiravir from cytidine in 63 % overall yield after recrystallization involving protection-deprotection steps (Scheme 1A).…”

Section: Molnupiravirmentioning

confidence: 99%

Evaluating Multienzyme Cascade Routes for Pharmaceutically Relevant Molecules

Naik,

Dheeraj,

Jeevani

et al. 2024

Eur J Org Chem

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The constant demand for sustainable approaches to pharmaceutical synthesis has thrived the enzyme catalysis (biocatalysis) field. The most sought‐after features like high specificity, environmentally benign, and biodegradable nature have rendered enzymatic processes predominantly eco‐friendly. Owing to these merits, biocatalysis is now being developed extensively to exploit their applications in designing alternate and sustainable synthetic routes for manufacturing pharmaceuticals, in line with green chemistry principles. Further, combining multiple enzymes in one‐pot is a highly efficient methodology as it eliminates intermediate isolation, shifts equilibrium in the forward direction, and proceeds in ambient aqueous conditions. This review highlights the importance of recently developed multienzyme cascade synthesis of pharmaceutically important bioactive molecules by relating them with their well‐known chemical route.

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“…23 Finally, a glycosylation route has been used to assemble suitable cytidine precursors that were then carried forth. 24,25 The precursors to the synthetic approaches are summarized in Fig. 2.…”

Section: Introductionmentioning

confidence: 99%

Two short approaches to the COVID-19 drug β-d-N⁴-hydroxycytidine and its prodrug molnupiravir

Persaud,

Sahu,

Neary

et al. 2024

Org. Biomol. Chem.

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Conversion of N-acyl amidines to amidoximes: a convenient synthetic approach to molnupiravir (EIDD-2801) from ribose

Abstract: A method for the preparation of molnupiravir (EIDD-2801) via regioselective conversion of an N-acyl-nucleoside intermediate, generated through stereoselective glycosylation of protected ribose and N4-acetyl cytosine, to an amidoxime.

Cited by 7 publications

References 18 publications

Impact of Disease States on the Oral Pharmacokinetics of EIDD-1931 (an Active Form of Molnupiravir) in Rats for Implication in the Dose Adjustment

Impact of Disease States on the Oral Pharmacokinetics of EIDD-1931 (an Active Form of Molnupiravir) in Rats for Implication in the Dose Adjustment

Evaluating Multienzyme Cascade Routes for Pharmaceutically Relevant Molecules

Two short approaches to the COVID-19 drug β-d-N⁴-hydroxycytidine and its prodrug molnupiravir

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Conversion of N-acyl amidines to amidoximes: a convenient synthetic approach to molnupiravir (EIDD-2801) from ribose

Abstract: A method for the preparation of molnupiravir (EIDD-2801) via regioselective conversion of an N-acyl-nucleoside intermediate, generated through stereoselective glycosylation of protected ribose and N4-acetyl cytosine, to an amidoxime.

Cited by 7 publications

References 18 publications

Impact of Disease States on the Oral Pharmacokinetics of EIDD-1931 (an Active Form of Molnupiravir) in Rats for Implication in the Dose Adjustment

Impact of Disease States on the Oral Pharmacokinetics of EIDD-1931 (an Active Form of Molnupiravir) in Rats for Implication in the Dose Adjustment

Evaluating Multienzyme Cascade Routes for Pharmaceutically Relevant Molecules

Two short approaches to the COVID-19 drug β-d-N4-hydroxycytidine and its prodrug molnupiravir

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Two short approaches to the COVID-19 drug β-d-N⁴-hydroxycytidine and its prodrug molnupiravir