Genesis of Dihydropyrimidinone Calcium Channel Blockers: Recent Progress in Structure-Activity Relationships and Other Effects

Singh, K. Chandramani; Arora, Deepshi; Singh, Sukhveer

doi:10.2174/138955709787001686

Cited by 74 publications

(5 citation statements)

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“…This acid-catalyzed cyclocondensation of urea, β-ketoesters and aromatic aldehydes to yield dihydropyrimidines has received significant attention, these products having pharmacological activity including calcium channel modulation, mitotic kinesin Eg5 inhibition, and antiviral and antibacterial activity [49–50]. The Biginelli reaction has been performed in flow previously as a route to densely functionalized heterocycles using HBr generated in a prior step as the catalyst for the reaction [51].…”

Section: Resultsmentioning

confidence: 99%

Raman spectroscopy as a tool for monitoring mesoscale continuous-flow organic synthesis: Equipment interface and assessment in four medicinally-relevant reactions

Hamlin¹,

Leadbeater²

2013

Beilstein J. Org. Chem.

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SummaryAn apparatus is reported for real-time Raman monitoring of reactions performed using continuous-flow processing. Its capability is assessed by studying four reactions, all involving formation of products bearing α,β-unsaturated carbonyl moieties; synthesis of 3-acetylcoumarin, Knoevenagel and Claisen–Schmidt condensations, and a Biginelli reaction. In each case it is possible to monitor the reactions and also in one case, by means of a calibration curve, determine product conversion from Raman spectral data as corroborated by data obtained using NMR spectroscopy.

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Section: Resultsmentioning

confidence: 99%

Raman spectroscopy as a tool for monitoring mesoscale continuous-flow organic synthesis: Equipment interface and assessment in four medicinally-relevant reactions

Hamlin¹,

Leadbeater²

2013

Beilstein J. Org. Chem.

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“…Pyrimidines, which have similar structural skeletons of pyridines, are identified as the vital component of nucleic acid and play an integral role as biologically significant antitumor, antiviral, and cardiovascular agents. Unlike light-sensitive and aromatic 1,4-dihydropyridines, the N-3 substituted DHPMs are shown to possess promising stability [ 38 ]. Analogous to 1,4 dihydropyridines, DHPMs have been shown to have a boat conformation for the modulation of their activity.…”

Section: Dihydropyrimidines As Calcium Channel Blockersmentioning

confidence: 99%

Synthesis of Dihydropyrimidines: Isosteres of Nifedipine and Evaluation of Their Calcium Channel Blocking Efficiency

et al. 2023

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Hypertension and cardiovascular diseases related to it remain the leading medical challenges globally. Several drugs have been synthesized and commercialized to manage hypertension. Some of these drugs have a dihydropyrimidine skeleton structure, act as efficient calcium channel blockers, and affect the calcium ions’ intake in vascular smooth muscle, hence managing hypertension. The synthesis of such moieties is crucial, and documenting their structure–activity relationship, their evolved and advanced synthetic procedures, and future opportunities in this area is currently a priority. Tremendous efforts have been made after the discovery of the Biginelli condensation reaction in the synthesis of dihydropyrimidines. From the specific selection of Biginelli adducts to the variation in the formed intermediates to achieve target compounds containing heterocylic rings, aldehydes, a variety of ketones, halogens, and many other desired functionalities, extensive studies have been carried out. Several substitutions at the C3, C4, and C5 positions of dihydropyrimidines have been explored, aiming to produce feasible derivatives with acceptable yields as well as antihypertensive activity. The current review aims to cover this requirement in detail.

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“…At present, the awareness of the Biginelli reaction relies on the announcement of a series of literature about the biological activities of DHPMs. These contain anti-proliferative (Treptow et al, 2015), antimicrobial (Tanay et al, 2015), anti-inflammatory (Bahekar & Shinde, 2004), antioxidant (de Vasconcelos et al, 2012), and calcium channel inhibition (Singh et al, 2009) activities.…”

Section: Introductionmentioning

confidence: 99%

Dihydropyrimidine derivatives as MDM2 inhibitors

Mehri,

Mahnam,

Sirous

et al. 2023

Chem Biol Drug Des

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One of the chief pathways to regulate p53 levels is MDM2 protein, which negatively controls p53 by direct inhibition. Many cancers overproduce MDM2 protein to interrupt p53 functions. Therefore, impeding MDM2's binding to p53 can reactivate p53 in tumor cells may suggest an effective approach for tumor therapy. Here, some Monastrol derivatives were designed in silico as MDM2 inhibitors, and their initial cytotoxicity was evaluated in vitro on MFC‐7 and MDA‐MB‐231 cells. A small library of Monastrol derivatives was created, and virtual screening (VS) was performed on them. The first‐ranked compound, which was extracted from VS, and the other six compounds 5a‐5f were selected to carry out the single‐docking and docking with explicit waters. The compound with the best average results was then subjected to molecular dynamic (MD) simulation. Compounds 5a‐5f were chemically synthesized and evaluated in vitro for their initial cytotoxicity on MFC‐7 and MDA‐MB‐231 cells by MTT assay. The best compound was compound 5d with ΔGave = −10.35 kcal/mol. MD simulation revealed a median potency in comparison with Nutlin‐3a. The MTT assay confirmed the docking and MD experiments. 5d has an IC50 of 60.09 μM on MCF‐7 cells. We attempted to use Monastrol scaffold as a potent inhibitor of MDM2 rather than an Eg5 inhibitor using in silico modification. The results obtained from the in silico and in vitro evaluations were noteworthy and warranted much more effort in the future.

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Genesis of Dihydropyrimidinone Calcium Channel Blockers: Recent Progress in Structure-Activity Relationships and Other Effects

Cited by 74 publications

References 0 publications

Raman spectroscopy as a tool for monitoring mesoscale continuous-flow organic synthesis: Equipment interface and assessment in four medicinally-relevant reactions

Raman spectroscopy as a tool for monitoring mesoscale continuous-flow organic synthesis: Equipment interface and assessment in four medicinally-relevant reactions

Synthesis of Dihydropyrimidines: Isosteres of Nifedipine and Evaluation of Their Calcium Channel Blocking Efficiency

Dihydropyrimidine derivatives as MDM2 inhibitors

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