Synthesis of novel calcium channel blockers with ACE2 inhibition and dual antihypertensive/anti-inflammatory effects: A possible therapeutic tool for COVID-19

Mahgoub, Shahenda; El-Sayed, Mohamed-I Kotb; Shehry, Mohamed F. El; Awad, Samir M.; Mansour, Yara E.; Fatahala, Samar S.

doi:10.1016/j.bioorg.2021.105272

Cited by 16 publications

(12 citation statements)

References 65 publications

(70 reference statements)

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“…Dihydropyrimidones ( IV in Figure a) have broad-ranging documented biological activity . Therefore, we synthesized , urea- and thiourea-containing analogues of compounds 4 , 12 , and 13 to examine the impact of exchanging guanidine’s exocyclic nitrogen with an oxygen or sulfur atom (compounds in Figure S3). These modifications would retain many of the steric and electronic properties of our bioactive dihydropyrimidines but eliminate their ability to donate hydrogen bonds from the exocyclic nitrogen.…”

Section: Results and Discussionmentioning

confidence: 99%

Synthesis and Characterization of Functionalized Amino Dihydropyrimidines Toward the Analysis of their Antibacterial Structure–Activity Relationships and Mechanism of Action

et al. 2022

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Antibiotic resistance among bacteria puts immense strain on public health. The discovery of new antibiotics that work through unique mechanisms is one important pillar toward combating this threat of resistance. A functionalized amino dihydropyrimidine was reported to exhibit antibacterial activity via the inhibition of dihydrofolate reductase, an underexploited antibacterial target. Despite this promise, little is known about its structure–activity relationships (SAR) and mechanism of activity. Toward this goal, the aza-Biginelli reaction was optimized to allow for the preparation of focused libraries of functionalized amino dihydropyridines, which in some cases required the use of variable temperature NMR analysis for the conclusive assignment of compound identity and purity. Antibacterial activity was examined using microdilution assays, and compound interactions with dihydrofolate reductase were assessed using antimicrobial synergy studies alongside in vitro enzyme kinetics, differential scanning fluorimetry, and protein crystallography. Clear antibacterial SAR trends were unveiled (MIC values from >64 to 4 μg/mL), indicating that this compound class has promise for future development as an antibacterial agent. Despite this, the in vitro biochemical and biophysical studies performed alongside the synergy assays call the antibacterial mechanism into question, indicating that further studies will be required to fully evaluate the antibacterial potential of this compound class.

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Section: Results and Discussionmentioning

confidence: 99%

Synthesis and Characterization of Functionalized Amino Dihydropyrimidines Toward the Analysis of their Antibacterial Structure–Activity Relationships and Mechanism of Action

et al. 2022

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“…Several specific, previously known, and newly developed calcium channel blockers target different channel types and host cell or viral compartments/pathways. A hypothetical mode of action using CCB treatment is the reduction of intracellular calcium levels, which would affect the viral calcium manipulation of host cells and inhibit viral host cell entry [ 137 , 144 , 145 , 163 , 164 ], has potential anti-inflammatory activity [ 86 , 142 , 144 ], and leads to relaxation of pulmonary smooth muscles, causing vasodilatory effects in the lungs and vascular system [ 138 ]. As knockout of STIM1, which results in increased STING activation, leads to enhanced IFN-I responses shown by Wu et al, the use of CCBs could possibly alter IFN-I levels and therefore also have positive effects on the resistance to SARS-CoV-2 infection.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, several potential calcium channel blockers together with ACE2 inhibitors, which suppress ACE2 binding to SARS-CoV-2 spike receptor-binding domain (RBD), and potential anti-inflammatory activity, mediate the reduction of IL-6 and C-reactive protein (CRP) production in LPS-stimulated THP-1 cells. The properties of the mentioned agents could be used as therapeutic tools for hypersensitive patients against COVID-19 infection and anti-inflammatory activities [ 144 ].…”

Section: Emerging Treatment Strategiesmentioning

confidence: 99%

Calcium Signals during SARS-CoV-2 Infection: Assessing the Potential of Emerging Therapies

Berlansky

Sallinger

Grabmayr

et al. 2022

Cells

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive-sense single-stranded RNA virus that causes coronavirus disease 2019 (COVID-19). This respiratory illness was declared a pandemic by the world health organization (WHO) in March 2020, just a few weeks after being described for the first time. Since then, global research effort has considerably increased humanity’s knowledge about both viruses and disease. It has also spawned several vaccines that have proven to be key tools in attenuating the spread of the pandemic and severity of COVID-19. However, with vaccine-related skepticism being on the rise, as well as breakthrough infections in the vaccinated population and the threat of a complete immune escape variant, alternative strategies in the fight against SARS-CoV-2 are urgently required. Calcium signals have long been known to play an essential role in infection with diverse viruses and thus constitute a promising avenue for further research on therapeutic strategies. In this review, we introduce the pivotal role of calcium signaling in viral infection cascades. Based on this, we discuss prospective calcium-related treatment targets and strategies for the cure of COVID-19 that exploit viral dependence on calcium signals.

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“…Similarly, N-type calcium channels are upregulated in SARS-CoV-2 infection leading to autonomic dysfunction and cardiac conductive abnormality. So, calcium channel blockers could be effective in the management of COVID-19-induced DSN (Mahgoub et al, 2021). Furthermore, Reddy and colleague reported the first case of POTS following mRNA COVID-19 vaccination in a 42 years old man (Reddy et al, 2021) suggesting that development of neutralizing antibodies following COVID-19 vaccination may trigger autoimmune reactions and development of DSN.…”

Section: Molecular Mechanism Of Dysautonomia In Covid-19mentioning

confidence: 99%

Covid-19-Induced Dysautonomia: A Menace of Sympathetic Storm

Al-Kuraishy¹,

Al-Gareeb²,

Qusti

et al. 2021

ASN Neuro

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Among the plethora of debilitating neurological disorders of COVID-19 syndrome in survivors, the scope of SARS-CoV-2-induced dysautonomia (DNS) is yet to be understood, though the implications are enormous. Herein, we present an inclusive mini-review of SARS-CoV-2-induced DNS and its associated complications. Although, the direct link between Covid-19 and DSN is still speculative, the hypothetical links are thought to be either a direct neuronal injury of the autonomic pathway or a para/post-infectious immune-induced mechanism. SARS-CoV-2 infection-induced stress may activate the sympathetic nervous system (SNS) leading to neuro-hormonal stimulation and activation of pro-inflammatory cytokines with further development of sympathetic storm. Sympathetic over-activation in Covid-19 is correlated with increase in capillary pulmonary leakage, alveolar damage, and development of acute respiratory distress syndrome. Furthermore, SARS-CoV-2 can spread through pulmonary mechanoreceptors and chemoreceptors to medullary respiratory center in a retrograde manner resulting in sudden respiratory failure. Taken together, DSN in Covid-19 is developed due to sympathetic storm and inhibition of Parasympathetic nervous system-mediated anti-inflammatory effect with development of cytokine storm. Therefore, sympathetic and cytokine storms together with activation of Renin-Angiotensin-System are the chief final pathway involved in the development of DSN in Covid-19.

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Synthesis of novel calcium channel blockers with ACE2 inhibition and dual antihypertensive/anti-inflammatory effects: A possible therapeutic tool for COVID-19

Abstract: Graphical abstract

Cited by 16 publications

References 65 publications

Synthesis and Characterization of Functionalized Amino Dihydropyrimidines Toward the Analysis of their Antibacterial Structure–Activity Relationships and Mechanism of Action

Synthesis and Characterization of Functionalized Amino Dihydropyrimidines Toward the Analysis of their Antibacterial Structure–Activity Relationships and Mechanism of Action

Calcium Signals during SARS-CoV-2 Infection: Assessing the Potential of Emerging Therapies

Covid-19-Induced Dysautonomia: A Menace of Sympathetic Storm

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