Fascinating Chemopreventive Story of Wogonin: A Chance to Hit on the Head in Cancer Treatment.

Cancer, global havoc, is a group of debilitating diseases that strikes family as well as society. Cancer cases are drastically increasing these days. Despite many therapies and surgical procedures available, cancer is still difficult to control due to limited effective therapies or targeted therapies. Natural products can produce lesser side effects to the normal cells, which are the major demerit of chemotherapies and radiation. Wogonin, a natural product extracted from the plant, Scutellaria baicalensis has been widely studied and found with a high caliber to tackle most of the cancers via several mechanisms that include intrinsic as well as extrinsic apoptosis signaling pathways, carcinogenesis diminution, telomerase activity inhibition, metastasis inhibition in the inflammatory microenvironment, anti-angiogenesis, cell growth inhibition and arrest of the cell cycle, increased generation of H2O2 and accumulation of Ca2+ and also as an adjuvant along with anticancer drugs. This article discusses the role of wogonin in various cancers, its synergism with various drugs, and the mechanism by which wogonin controls tumor growth.

COVID-19 and Domestic Animals: Exploring the Species Barrier Crossing, Zoonotic and Reverse Zoonotic Transmission of SARS-CoV-2.

BACKGROUND: To date, more than thirty animals have been tested positive for SARS-CoV-2; all of them infected by humans with COVID-19. Some animal experiments suggested the possibility of animal to animal transmission of SARS-CoV-2 that was seen in some cases of infected animals. Animal to human transmission was considered unlikely until investigations revealed the possibility of mink to human transmission of SARS-CoV-2 in the Netherlands. OBJECTIVE: The current study aims at highlighting the predominance of SARS-CoV-2 infection in various animal species, reverse zoonotic transmission and proposing possible animal models that might aid in the study and development of a vaccine against Covid-19. METHODS: The authors have gathered information on various animal species infected with SARS-CoV-2 and possible tests conducted via online news reports, websites and Scopus indexed journals. RESULTS: The study of the susceptibility of SARS-CoV-2 to domestic animals concluded that pigs, chicken, and ducks were not vulnerable to Covid-19; dogs showed less susceptibility to SARS-CoV-2 and cats as well as ferrets were seen susceptible to Covid-19. SARS-CoV-2 has been seen crossing the species barrier, infecting humans from the wild with the yet unclear source, spreading from humans to humans quickly, humans to animals, animals to animals, and is likely to spread from animals to humans even though minimally. Animals appear somewhat resistant to SARS-CoV-2 transmission compared to humans who globally crossed eight million infection cases, and the infected animals mostly do not show many complications and recover quickly. CONCLUSION: Precautions are advised to prevent human to animal transmission of the virus, and in some areas, to avoid animal to human spread of the virus. Further monitoring is required to assess the SARS-CoV-2 infection in animals as COVID-19 is a rapidly evolving condition worldwide. Cats and ferrets have physiological resemblance and genome sequencing studies propose the possibility of these species to be used as animal models for investigating the SARS-CoV-2 infection and this might aid in further studies and vaccine development against Covid-19.

Emerging therapeutic potentials of dual-acting MAO and AChE inhibitors in Alzheimer's and Parkinson's diseases.

No drug has been approved to prevent neuronal cell loss in patients suffering from Parkinson's disease (PD) or Alzheimer's disease (AD); despite increased comprehension of the underlying molecular causes, therapies target cognitive functional improvement and motor fluctuation control. Drug design strategies that adopt the "one protein, one target" philosophy fail to address the multifactorial aetiologies of neurodegenerative disorders such as AD and PD optimally. On the contrary, restoring neurotransmitter levels by combined combinatorial inhibition of cholinesterases, monoamine oxidases, and adenosine A2A A receptors, in conjunction with strategies to counter oxidative stress and beta-amyloid plaque accumulation, would constitute a therapeutically robust, multitarget approach. This extensive review delineates the therapeutic advantages of combining dual-acting molecules that inhibit monoamine oxidases and cholinesterases and/or adenosine A2A A receptors, and describes the structure-activity relationships of compound classes that include, but are not limited to, alkaloids, coumarins, chalcones, donepezil-propargylamine conjugates, homoisoflavonoids, resveratrol analogs, hydrazones, and pyrazolines. In the wake of recent advances in network biology, in silico approaches, and omics, this review emphasizes the need to consider conceptually informed research strategies for drug discovery, in the context of the mounting burden posed by chronic neurodegenerative diseases with complex aetiologies and pathophysiologies involving multiple signalling pathways and numerous drug targets.

Potent and highly selective dual-targeting monoamine oxidase-B inhibitors: Fluorinated chalcones of morpholine versus imidazole.

Two series of fluorinated chalcones containing morpholine and imidazole-based compounds (f1-f8) were synthesized and evaluated for recombinant human monoamine oxidase (MAO)-A and -B as well as acetylcholinesterase inhibitory activities. Our results indicate that morpholine containing chalcones are highly selective MAO-B inhibitors having reversibility properties. All the imidazole-based fluorinated chalcones showed weak MAO inhibitions in both isoforms. Among the tested compounds, (2E)-3-(3-fluorophenyl)-1-[4-(morpholin-4-yl)phenyl]prop-2-en-1-one (f2) showed potent inhibitory activity for recombinant human MAO-B (IC50 = 0.087 µM) with a high selectivity index (SI) of 517.2. In the recovery experiments using dialysis, the residual activity of MAO-B inhibited by f2 was close to that with the reversible reference inhibitor. Inhibition assays revealed that the Ki values of f1 and f2 for MAO-B were 0.027 and 0.020 µM, respectively, with competitive patterns. All the morpholine-based compounds (f1-f4) showed moderate inhibition toward acetylcholinesterase with IC50 values ranging between 24 and 54 µM. All morpholine-containing compounds exhibit good blood-brain barrier permeation in the PAMPA method. The rational approach regarding the highly selective MAO-B inhibitor f2 was further ascertained by induced fit docking and molecular dynamics simulation studies.

Fe3 O4 nanoparticles mediated synthesis of novel spirooxindole-dihydropyrimidinone molecules as Hsp90 inhibitors.

Heat shock protein 90 (Hsp90) is a validated molecular chaperone considered as the new key recipient for cancer intervention. The current study illustrates the synthesis of novel spirooxindole-dihydropyrimidinones (4a-j) by Fe3 O4 nanoparticles intervened synthesis and their Hsp90 ATPase inhibitory activity was investigated by the malachite green assay. All the compounds in the study demonstrated a moderate to potent ATPase inhibitory profile, with IC50 values ranging from 0.18 to 6.80 µM. Compounds 4j, 4h, 4f, and 4i exhibited maximum inhibitory potential with IC50 values of 0.18, 0.20, 0.35, and 0.55 µM, respectively. They were found to be better than the standard drug, geldanamycin (Hsp9 ATPase inhibition IC50 = 0.90 µM). Compounds 4h and 4j with IC50 values of 22.82 ± 0.532, 20.78 ± 0.234 and 21.32 ± 0.765, 28.43 ± 0.653 µM showed significantly greater potencies against the MCF-7 and HepG2 cell lines, respectively. Compound 4j showed good antioxidant activities in the DPPH test and H2 O2 assay (IC50 = 20.13.23 ± 0.32 and 23.27 ± 0.32 µg/mL) when compared with the standard ascorbic acid (IC50 = 19.16 ± 0.20 and 20.66 ± 1.09 µg/mL). A molecular docking study was performed to observe the binding efficiency and steric interactions of the lead moiety.

Cholinesterase Inhibitory Activities of Selected Halogenated Thiophene Chalcones.

BACKGROUND: Dual-acting human monoamine oxidase B (hMAO-B) and cholinesterase (ChE) inhibitors are more effective than the classic one-drug one-target therapy for Alzheimer's disease (AD). METHODS: The ChE inhibitory ability of some halogenated thiophene chalcone-based molecules known to be selective hMAO-B inhibitors was evaluated. RESULTS: Based on the IC50 values, the selected compounds were found to moderately inhibit ChE, with IC50 values in the range of 14-70 µM. Among the synthesised molecules, T8 and T6 showed the most potent inhibitory activity against AChE and BChE, respectively. CONCLUSION: Taken together, the data revealed that T8 could be further optimized to enhance its AChE inhibitory activity.

Synthesis, Biochemistry, and Computational Studies of Brominated Thienyl Chalcones: A New Class of Reversible MAO-B Inhibitors.

A series of (2E)-1-(5-bromothiophen-2-yl)-3-(para-substituted phenyl)prop-2-en-1-ones (TB1-TB11) was synthesized and tested for inhibitory activity toward human monoamine oxidase (hMAO). All compounds were found to be competitive, selective, and reversible toward hMAO-B except (2E)-1-(5-bromothiophen-2-yl)-3-(4-nitrophenyl)prop-2-en-1-one (TB7) and (2E)-1-(5-bromothiophen-2-yl)-3-(4-chlorophenyl)prop-2-en-1-one (TB8), which were selective inhibitors of hMAO-A. The most potent compound, (2E)-1-(5-bromothiophen-2-yl)-3-[4-(dimethylamino)phenyl]prop-2-en-1-one (TB5), showed the best inhibitory activity and higher selectivity toward hMAO-B, with Ki and SI values of 0.11±0.01 µm and 13.18, respectively. PAMPA assays for all compounds were carried out in order to evaluate the capacity of the compounds to cross the blood-brain barrier. Moreover, the most potent MAO-B inhibitor, TB5, was found to be nontoxic at 5 and 25 µm, with 95.75 and 84.59 % viability among cells, respectively. Molecular docking simulations were carried out to understand the crucial interactions responsible for selectivity and potency.

Monoamine Oxidase Inhibitory Action of Chalcones: A Mini Review.

INTRODUCTION: Chalcones are one of the major classes of naturally occurring compounds and have a vast significance in medicinal chemistry, presenting with a wide scope of pharmacological actions. DISCUSSION: The present review focused our attention onto the monoamine oxidase inhibitory activity of natural and synthetic chalcones. The review also emphasises the structure-activity relationship studies and molecular recognition of chalcones towards MAO-A and B inhibition. CONCLUSION: Many of the studies clearly revealed that most of the chalcones showed selective, reversible and potent MAO-B inhibition compared to MAO-A. Recent studies also showed that heteroaryl-based chalcones are potent MAO-A inhibitors.

Pharmacophore Modeling, 3D-QSAR and Molecular Docking of Furanochalcones as Inhibitors of Monoamine Oxidase-B.

Monoamine oxidase B inhibitors are of particular importance in the treatment of neurodegenerative disorders such as Alzheimer's and Parkinson's disease. Herein described is pharmacophore generation and atom-based 3D-QSAR analysis of previously reported furan based MAO-B inhibitors in order to get insight into their structural requirements responsible for high affinity. The best pharmacophore model generated with the five-point hypotheses of ADHRR: hydrogen bond acceptor (A), hydrogen bond donor (D), hydrophobic (H) and two aromatic rings (R1 & R2). On the basis of generated model, a statistically valid 3D-QSAR with good predictability was developed. Molecular docking of lead compound showed binding energy of -8.66 kcal/mol with a predicted inhibition constant of 0.448 µM towards MAO-B.

Psychomotor Seizure Screening and in vitro Neuroprotection Assay of Hydrazones Derived from 2-Acetyl Thiophene.

BACKGROUND: Hydrazone core is a versatile structural linker for the development of various classes of antiepileptic agents. The aim of this study was to investigate the anticonvulsant activity of thiophene based hydrazones according to the antiepileptic drug development program protocol. METHODS: The maximal electroshock-induced seizure and 6 Hz "Psychomotor" seizure test models in mice were performed. Additionally, the active compounds in the screening test were subsequently subjected to the maximal electroshock-induced seizure test that allowed determination of their median effective doses and median toxic doses. The most active compound was also subjected to the In vitro Hippocampal slice culture neuroprotection assay. RESULTS: Among the synthesized compounds, 1-(thiophen-2-yl) ethylidene] hydrazine carboxamides (THb) and 1-(thiophen-2-yl) ethylidene] hydrazine carbothioamide (THc) showed a broad-spectrum anticonvulsant activity since they were active in both maximal electroshock-induced seizure and 6Hz-Psychomotor induced seizure models with no neurotoxicity. In the mice maximal electroshock-induced seizure screen, compound THb gave an ED50 of 11.8 mg/kg and a TD50 of 39.47 mg/kg, resulting in a good protection index (PI), that is, TD50/ED50, of 3.3 when compared to Phenobarbital and Valproate. THb (100µM) was also found to be effectively suppressing network hyperexcitability in the in vitro mEC-HC spontaneous bursting model, as determined by effects on spontaneous burst activity and duration. CONCLUSION: The suggested pharmacophore model for lead compounds from thiophene based hydrazones is explained by the hydrophobic domain-thiophene, electron donor-imine and hydrogen bonding domain-carboxamide or carbothioamide unit.

Hydrazones as a privileged structural linker in antitubercular agents: a review.

Hydrazones are a versatile linker of connecting various classes of organic compounds with a unique structural feature of hydrogen bonding donor and the hydrogen bonding acceptor region. An extensive number of research has been carried out on hydrazone derivatives as a potent class of antitubercular agents. The present review focuses on the chemistry, antitubercular activity and structure activity relationship (SAR) of diverse classes of phenyl and heterocyclic based hydrazones.

Design, Synthesis, Toxicity Estimation and Molecular Docking Studies of N-(furan-2-yl)-1-(5-substituted) phenyl-1,3,4-oxadiazol-2-yl) methanimine as Antitubercular Agents.

A series of novel N-(furan-2-yl)-1-(5-substituted) phenyl-1,3,4-oxadiazol-2-yl) methanimines (Fa-e) were synthesized and evaluated for antitubercular activity against Mycobacterium tuberculosis (H37Rv) strain by using alamar blue assay. The synthesized compounds were characterized based on IR, (1)HMR and mass spectral analysis. The toxicity profile was predicted by organic chemistry portal, a web based application for predicting in silico absorption, distribution, metabolism, excretion and toxicity, and the novel derivatives under study did not show any toxicity issues. The mechanism of action of the titled derivatives was predicted by docking on the Mycobacterium tuberculosis Enoyl-ACP reductase enzyme. The docking study concluded that Fb and Fa possessed good binding energy indicating more prominent interaction towards the active sites NAD and TYR 158. The antitubercular studies showed that the both Fa and Fb possessed significant activity with the MIC as low as 3.125 µg/ml.

Plant secondary metabolites- potent inhibitors of monoamine oxidase isoforms.

Target of monoamine oxidase inhibitions are considered as the treatment of depressive states and neurodegenerative disorders, including Parkinson's and Alzheimer's diseases. Many medicinal chemistry research groups are actively working in this area for the development of most promising selective MAO inhibitors. Many plant isolates also showed remarkable MAO inhibition in recent years. The objective of this review is to identify the major MAO inhibitors secondary metabolites from plants like flavonoids, alkaloids and xanthones class of compounds.

Diuretic activity of leaves of garcinia cambogia in rats.

The present study was undertaken to establish the diuretic activity of ethanol and aqueous extract of dried leaves of Garcinia cambogia in rats. Aqueous and ethanol extracts of leaves were administered to experimental rats orally at doses of 100 and 200 mg/kg and compared with furosemide (20 mg/kg, intraperitoneally) as the standard. The parameters measured for diuretic activity were total urine volume, urine concentration electrolytes such as sodium, potassium and chloride have been evaluated . The rats treated with ethanol extract of Garcinia cambogia and aqueous extract of Garcinia cambogia in a dose of 100 and 200 mg/kg showed higher urine output when compared to the respective control. Both ethanol and aqueous extracts have showed a significant dose-dependent increase in the excretion of electrolytes when compared to the control group.