scholarly journals Multifunctional Isosteric Pyridine Analogs-Based 2-Aminothiazole: Design, Synthesis, and Potential Phosphodiesterase-5 Inhibitory Activity

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 902
Author(s):  
Abdel Haleem M. Hussein ◽  
Ahmed A. Khames ◽  
Abu-Bakr A. El-Adasy ◽  
Ahmed A. Atalla ◽  
Mohamed Abdel-Rady ◽  
...  
Keyword(s):  
Pde5 Inhibitor ◽  
Docking Study ◽  
Cyclic Guanosine Monophosphate ◽  
Molecular Shape ◽  
Guanosine Monophosphate ◽  
Molecular Docking Study ◽  
Reference Drug ◽  
Arterial Blood ◽  
Severe Hypotension

The elaboration of new small molecules that target phosphodiesterase enzymes (PDEs), especially those of type 5 (PDE5), is an interesting and emerging topic nowadays. A new series of heterocycle-based aminothiazoles were designed and synthesized from the key intermediate, 3-oxo-N-(thiazol-2-yl)butanamide (a PDE5 inhibitor that retains its amidic function), as an essential pharmacophoric moiety. The PDE5 inhibitors prevent the degradation of cyclic guanosine monophosphate, thereby causing severe hypotension as a marked side effect. Hence, an in vivo testing of the target compounds was conducted to verify its relation with arterial blood pressure. Utilizing sildenafil as the reference drug, Compounds 5, 10a, and 11b achieved 100% inhibitions of PDE5 without significantly lowering the mean arterial blood pressures (115.95 ± 2.91, 110.3 ± 2.84, and 78.3 ± 2.57, respectively). The molecular docking study revealed that the tested compounds exhibited docking poses that were similar to that of sildenafil (exploiting the amide functionality that interacted with GLN:817:A). The molecular shape and electrostatic similarity revealed a comparable physically achievable electrostatic potential with the reference drug, sildenafil. Therefore, these concomitant results revealed that the tested compounds exerted sildenafil-like inhibitory effects (although without its known drawbacks) on blood circulation, thus suggesting that the tested compounds might represent a cornerstone of beneficial drug candidates for the safe treatment for erectile dysfunction.

scholarly journals Synthesis, Anti-Inflammatory Activity, and In Silico Study of Novel Diclofenac and Isatin Conjugates

2018 ◽  
Vol 2018 ◽  
pp. 1-11
Author(s):  
Musab Mohamed Ibrahim ◽  
Tilal Elsaman ◽  
Mosab Yahya Al-Nour
Keyword(s):  
Virtual Screening ◽  
Condensation Reaction ◽  
Docking Study ◽  
Positive Control ◽  
Inflammatory Activity ◽  
Molecular Docking Study ◽  
Design Synthesis ◽  
Chemical Structures ◽  
Anti Inflammatory

The design, synthesis, and development of novel non-steroidal anti-inflammatory drugs (NSAIDs) with better activity and lower side effects are respectable area of research. Novel Diclofenac Schiff’s bases (M1, M2, M4, M7, and M8) were designed and synthesized, and their respective chemical structures were deduced using various spectral tools (IR, 1H NMR, 13C NMR, and MS). The compounds were synthesized via Schiff’s condensation reaction and their anti-inflammatory activity was investigated applying the Carrageenan-induced paw edema model against Diclofenac as positive control. Percentage inhibition of edema indicated that all compounds were exhibiting a comparable anti-inflammatory activity as Diclofenac. Moreover, the anti-inflammatory activity was supported via virtual screening using molecular docking study. Interestingly compound M2 showed the highest in vivo activity (61.32% inhibition) when compared to standard Diclofenac (51.36% inhibition) as well as the best binding energy score (-10.765) and the virtual screening docking score (-12.142).

scholarly journals The constitutively active PKG II mutant effectively inhibits gastric cancer development via a blockade of EGF/EGFR-associated signalling cascades

2018 ◽  
Vol 10 ◽  
pp. 175883401775163 ◽  
Author(s):  
Yan Wu ◽  
Miaomiao Yuan ◽  
Wenbin Su ◽  
Miaolin Zhu ◽  
Xiaoyuan Yao ◽  
...  
Keyword(s):  
Growth Factor Receptor ◽  
Cyclic Guanosine Monophosphate ◽  
Inhibitory Effect ◽  
Guanosine Monophosphate ◽  
Tumour Development ◽  
Gastric Tumour ◽  
Signalling Cascades ◽  
Constitutively Active

Type II cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG II) is a membrane-anchored enzyme expressed mainly in the intestinal mucosa and the brain, and is associated with various physiological or pathological processes. Upregulation of PKG II is known to induce apoptosis and inhibit proliferation and metastasis of cancer cells. The inhibitory effect of PKG II has been shown to be dependent on the inhibition of the activation of epidermal growth factor receptor (EGFR) and blockade of EGFR downstream signal transduction in vitro. However, it remains unclear whether similar phenomena/mechanisms exist in vivo and whether these effects are independent of cGMP or cGMP analogues. In the present work, nude mice with transplanted orthotopic tumours were infected with adenovirus encoding cDNA of constitutively active PKG II mutant (Ad-a-PKG II) and the effect of constitutively active PKG II (a-PKG II) on tumour development was detected. The results showed that a-PKG II effectively ameliorated gastric tumour development through delaying the growth, inducing the apoptosis, and inhibiting the metastasis and angiogenesis. The effect was related to blockade of EGFR activation and abrogation of the downstream signalling cascades. These findings provide novel insight which will benefit the development of new cancer therapies.

scholarly journals cGAS-mediated autophagy protects the liver from ischemia-reperfusion injury independently of STING

2018 ◽  
Vol 314 (6) ◽  
pp. G655-G667 ◽  
Author(s):  
Zhao Lei ◽  
Meihong Deng ◽  
Zhongjie Yi ◽  
Qian Sun ◽  
Richard A. Shapiro ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Adenosine Monophosphate ◽  
Cyclic Guanosine Monophosphate ◽  
Protective Role ◽  
Guanosine Monophosphate ◽  
Independent Manner

Liver ischemia-reperfusion (I/R) injury occurs through induction of oxidative stress and release of damage-associated molecular patterns (DAMPs), including cytosolic DNA released from dysfunctional mitochondria or from the nucleus. Cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) synthase (cGAS) is a cytosolic DNA sensor known to trigger stimulator of interferon genes (STING) and downstream type 1 interferon (IFN-I) pathways, which are pivotal innate immune system responses to pathogen. However, little is known about the role of cGAS/STING in liver I/R injury. We subjected C57BL/6 (WT), cGAS knockout (cGAS−/−), and STING-deficient (STINGgt/gt) mice to warm liver I/R injury and that found cGAS−/− mice had significantly increased liver injury compared with WT or STINGgt/gt mice, suggesting a protective effect of cGAS independent of STING. Liver I/R upregulated cGAS in vivo and also in vitro in hepatocytes subjected to anoxia/reoxygenation (A/R). We confirmed a previously published finding that hepatocytes do not express STING under normoxic conditions or after A/R. Hepatocytes and liver from cGAS−/− mice had increased cell death and reduced induction of autophagy under hypoxic conditions as well as increased apoptosis. Protection could be restored in cGAS−/− hepatocytes by overexpression of cGAS or by pretreatment of mice with autophagy inducer rapamycin. Our findings indicate a novel protective role for cGAS in the regulation of autophagy during liver I/R injury that occurs independently of STING. NEW & NOTEWORTHY Our studies are the first to document the important role of cGAS in the acute setting of sterile injury induced by I/R. Specifically, we provide evidence that cGAS protects liver from I/R injury in a STING-independent manner.

scholarly journals Identification of Potent Inhibitors of COVID-19 Main Protease Enzyme by Molecular Docking Study

2020 ◽  
Author(s):  
pooja singh ◽  
Angkita Sharma ◽  
Shoma Paul Nandi
Keyword(s):  
Molecular Docking ◽  
Antiviral Drug ◽  
Cyclopiazonic Acid ◽  
Docking Study ◽  
Molecular Docking Study ◽  
Docking Score ◽  
Protease Enzyme ◽  
Main Protease

<p>Within the span of a few months, the severe acute respiratory syndrome coronavirus, COVID-19 (SARS-CoV-2), has proven to be a pandemic, affecting the world at an exponential rate. It is extremely pathogenic and causes communicable infection in humans. Viral infection causes difficulties in breathing, sore throat, cough, high fever, muscle pain, diarrhea, dyspnea, and may lead to death. Finding a proper drug and vaccines against this virus is the need of the hour. The RNA genome of COVID19 codes for the main protease M<sup>pro</sup>, which is required for viral multiplication. To identify possible antiviral drug(s), we performed molecular docking studies. Our screen identified ten biomolecules naturally present in <i>Aspergillus flavus</i> and <i>Aspergillus oryzae</i> fungi. These molecules include Aspirochlorine, Aflatoxin B1, Alpha-Cyclopiazonic acid, Sporogen, Asperfuran, Aspergillomarasmine A, Maltoryzine, Kojic acid, Aflatrem and Ethyl 3-nitropropionic acid, arranged in the descending order of their docking score. Aspirochlorine exhibited the docking score of – 7.18 Kcal/mole, higher than presently used drug Chloroquine (-6.2930522 Kcal/mol) and out of ten ligands studied four has docking score higher than chloroquine. These natural bioactive compounds could be tested for their ability to inhibit viral growth <i>in- vitro</i> and <i>in-vivo</i>.<b> </b></p>

scholarly journals New Approaches in Oncology for Repositioning Drugs: The Case of PDE5 Inhibitor Sildenafil

2021 ◽  
Vol 11 ◽  
Author(s):  
Marian Cruz-Burgos ◽  
Alberto Losada-Garcia ◽  
Carlos D. Cruz-Hernández ◽  
Sergio A. Cortés-Ramírez ◽  
Ignacio Camacho-Arroyo ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Pde5 Inhibitor ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Systemic Hypertension ◽  
Pde5 Inhibitors ◽  
Development Costs ◽  
Cgmp Signaling ◽  
Molecular Effects ◽  
Approved Drugs

The use of already-approved drugs to treat new or alternative diseases has proved to be beneficial in medicine, because it reduces both drug development costs and timelines. Most drugs can be used to treat different illnesses, due their mechanisms of action are not restricted to one molecular target, organ or illness. Diverging from its original intent offers an opportunity to repurpose previously approved drugs to treat other ailments. This is the case of sildenafil (Viagra), a phosphodiesterase-5 (PDE5) inhibitor, which was originally designed to treat systemic hypertension and angina but is currently commercialized as erectile dysfunction treatment. Sildenafil, tadalafil, and vardenafil are PDE5 inhibitors and potent vasodilators, that extend the physiological effects of nitric oxide and cyclic guanosine monophosphate (cGMP) signaling. Although most of the biological implications of these signaling regulations remain unknown, they offer a large therapeutic potential for several diseases. In addition, some PDE5 inhibitors’ molecular effects seem to play a key role in different illnesses such as kidney disease, diabetes mellitus, and cancer. In this review, we discuss the molecular effects of PDE5 inhibitors and their therapeutic repurposing in different types of cancer.

scholarly journals 2-Arachidonoylglycerol as an Endogenous Cue Negatively Regulates Attachment of the Mussel Perna viridis

2021 ◽  
Vol 8 ◽  
Author(s):  
Qi Dai ◽  
Zhi-Xuan Wang ◽  
Yan-Qing Sheng ◽  
Zhi-Wen Wu ◽  
Yan Qiu ◽  
...  
Keyword(s):  
Marine Invertebrates ◽  
Endocannabinoid System ◽  
Cyclic Guanosine Monophosphate ◽  
Negative Regulation ◽  
Guanosine Monophosphate ◽  
Perna Viridis ◽  
Cgmp Pathway ◽  
Arachidonoyl Glycerol ◽  
Putative Mechanism

Endocannabinoids play important roles in the functioning of various physiological systems in humans and non-mammalian animals, including invertebrates. However, information concerning their roles in physiological functions in members of the phylum Mollusca is scarce. Here the hypothesis that the endocannabinoids are involved in mediating settlement of marine invertebrates was tested. Two endocannabinoids [N-arachidonoyl ethanolamide (AEA) and 2-arachidonoyl glycerol (2-AG)], and two endocannabinoid-like lipids [N-Oleoylethanolamide (OEA) and N-Palmitoylethanolamide (PEA)] were detected in the green mussel Perna viridis. In particular, 2-AG was present at significantly higher levels in unattached P. viridis compared with attached mussels. The in vivo level of 2-AG was inversely correlated with the attachment activity of P. viridis. Furthermore, exposure to synthetic 2-AG inhibited attachment of P. viridis in a reversible manner. Transcriptomic analysis suggested that up-regulation of 2-AG synthase (Phospholipase C-β, PLC-β) and down-regulation of its degrading enzyme (Monoacylglycerol lipase, MAGL) resulted in higher levels of 2-AG in unattached mussels. A putative mechanism for the negative regulation of mussel attachment by 2-AG is proposed that involves a Ca2+- Nitric oxide (NO)- cyclic guanosine monophosphate (cGMP) pathway. This study broadens our understanding of the evolution and roles of the endocannabinoid system in animals, and reveals an endogenous regulatory cue for mussel attachment.

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