Could Small Neurotoxins-Peptides be Expressed during SARS-CoV-2 Infection?

: SARS-CoV-2 pathogenesis has been recently extended to human central nervous system (CNS), in addition to nasopharyngeal truck, eye, lung and gut. The recent literature highlights that some SARS-CoV-2 spike glycoprotein regions homologous to neurotoxin-like peptides might bind to human nicotinic Acetyl-Choline Receptors (nAChRs). Spike-nAChR interaction can probably cause dysregulation of CNS and cholinergic anti-inflammatory pathways and uncontrolled immune-response, both associated to a severe COVID-19 pathophysiology. Herein, we hypothesize that inside the Open Reading Frame (ORF) region of spike glycoprotein, the RNA polymerase can translate small neurotoxic peptides by means of a “jumping mechanism” already demonstrated in other coronaviruses. These small peptides can bind the snAChRs instead of Spike glycoproteins. A striking homology occurred between these small peptides observed by sequence retrieval and proteins alignment. Acting as nAChRs antagonists, these small peptides (conotoxins) could be the explanation for the extrapulmonary clinical manifestations (neurological, hemorrhagic and thrombotic expressions, the prolonged apnea, the cardiocirculatory collapse, the heart arrhythmias, the ventricular tachycardia, the body temperature alteration, the electrolyte K+ imbalance and finally the significant reduction of butyryl cholinesterase (BuChE) plasma levels, as observed in COVID-19 patients. Several factors might induce the expression of these small peptides, including microbiota. The main hypothesis regarding the presence of these small peptides opens a new scenario on the etiology of COVID-19 clinical symptoms observed so far, including the neurological manifestations.

Synthesis of Sulfanoquinoxaline-2,3-Dione Hydrazones Derivatives as a Selective Inhibitor for Acetylcholinesterase and Butyryl Cholinesterase

Some Sulfanoquinoxaline-2,3-diones hydrazone derivatives (1-8) were synthesized from the reactions of 2,3-dioxoquinoxaline-6-sulfonohydrazine with seven substituted benzaldehydes and acetophenone. All the synthesized compounds were biologically evaluated against cholinesterase’s (acetylcholinesterase and butyryl cholinesterase). Compounds 1-8 were found to be a good selective inhibitor for acetylcholinesterase and butyryl cholinesterase. Among the series, compounds 3 (IC50 = 75 ± 10 µg/mL) and 5 (IC50 = 80 ± 10 µg/mL) were found to be the most active inhibitors against acetylcholinesterase, while compounds 6 (IC50 = 110 ± 10 µg/mL), 8 (IC50 = 130 ± 10 µg/mL) and 7 (IC50 = 150 ± 10 µg/mL), were found to be most active inhibitor against butyryl cholinesterase. The IC50 values for all the synthesized compounds were lower than standard, eserine (IC50 = 70 ± 20 µg/mL). Their considerable acetylcholinesterase and butyryl cholinesterase inhibitory activities make them a good candidate for the development of selective acetylcholinesterase and butyryl cholinesterase inhibitors.

Synthesis of Some Phenylisoindoline-1,3-Diones and their Acetylcholinesterase and Butyryl Cholinesterase Inhibitory Activities

Aims: To synthesize some phthalimides derivatives and evaluate the compounds for their possible biological properties. Methods: The substituted phenylisoindoline-1,3-dione were synthesized from the reactions of N-phenyl phthalimide with different substituted aromatic aldehyde. The synthesized compounds were characterized using nuclear magnetic resonance spectroscopic analysis. The acetylcholinesterase and butyryl cholinesterase inhibitions were determined by Spectro photochemical analysis of acetylthiocholine and butyryl choline chloride. Results: Compounds 6 (IC50 = 30±3 µg/mL) and 4 (IC50 = 141±60 µg/mL) were found to be the most active inhibitors against acetylcholinesterase, while compounds 4 (IC50 = 102±10 µg/mL), 5 (IC50 = 105 ± 20 µg/mL) and 2 (IC50 = 190 ± 10 µg/mL), were found to be most active inhibitor against butyryl cholinesterase. Conclusion: The considerable acetylcholinesterase and butyryl cholinesterase inhibitory activities of the synthesized compounds makes them good candidates for the development of selective acetylcholinesterase and butyryl cholinesterase inhibitors.

Design, Synthesis and Biological Activities of Some phthalimides Derivatives

Aims: To synthesize some phthalimides derivatives and evaluate the compounds for their possible biological properties. Methods: The substituted phenylisoindoline-1,3-dione were synthesized from the reactions of N-phenyl phthalimide with different substituted aromatic aldehyde. The synthesized compounds were characterized using nuclear magnetic resonance spectroscopic analysis. The Nitric oxide and Ferric reducing antioxidant properties (FRAP) were determined by spectrophochemical method. Results: The IC50 values for all the synthesized compounds were lower than standard, eserine (IC50 = 15 ± 2 µg/mL) against Nitric oxide inhibition. Compounds 3 (FRAP = 205±8 µg/ML) and 6 (FRAP = 118±1 µg/ML) were found to exhibit higher FRAP analysis results which were comparable to the results obtained for serine. (FRAP = 202±7 µg/ML). Conclusion: The considerable activity of the compounds shown by its Nitric oxide and Ferric reducing antioxidant properties (FRAP) makes them good candidates for the development of selective acetylcholinesterase and butyryl cholinesterase inhibitors.

IMPACT OF LEPIDIUMS ATIVUM NANO-FORMULATION ON SOME BIOLOGICAL AND BIOCHEMICAL ACTIVITIES OF SCHISTOCERCA GREGARIA (ORTHOPTERA: ACRIDIDAE)

The effect of nano emulsions, of Garden Cress seed oil Lepidium sativum and its bulk form have been studied against some biological and biochemical aspects of 5th instar nymph of Schistocerca gregaria. Topical application of both nano and crude formulations of L. sativum in concentrations of 5 and 10% showed significant elongation of nymphal duration period. Mortality percentages increased as well as nymphal malformations and their unsuccessful molting when compared with control nymphs. Enzymatic activities seemed to be affected by both formulations. Butyryl cholinesterase activity increased significantly as a result of treatments after three days post treatment. Alkaline phosphatase activity increased significantly after 48 hours then decreased after 72 hours when compared with control nymphes. Total protein seemed to be not affected by treatments. Results proved that the topical application of L. sativum nano-formulation and its bulk form on the 5thnymphal instar of S. gregaria was novel and promised. The results should be taken into consideration for future research.

Anticholinesterase Activities of Different Solvent Extracts of Brewer’s Spent Grain

Cholinesterases, involved in acetylcholine catabolism in the central and peripheral nervous system, have been strongly linked with neurodegenerative diseases. Current therapeutic approaches using synthetic drugs present several side effects. Hence, there is an increasing research interest in naturally-occurring dietary polyphenols, which are also considered efficacious. Food processing by-products such as brewer’s spent grain (BSG) would be a potential bio-source of polyphenols. In this study, polyphenol-rich BSG extracts using 60% acetone and 0.75% NaOH solutions were generated, which were further subjected to liquid–liquid partitioning using various organic solvents. The water-partitioned fractions of the saponified extracts had the highest total polyphenol content (6.2 ± 2.8mgGAE/g dw) as determined by Folin–Ciocalteu reagent, while the LC-MS/MS showed ethyl acetate fraction with the highest phenolics (2.9 ± 0.3mg/g BSG dw). The best inhibitions of acetyl- (37.9 ± 2.9%) and butyryl- (53.6 ± 7.7%) cholinesterases were shown by the diethyl ether fraction of the saponified extract. This fraction contained the highest sum of quantified phenolics (99 ± 21.2µg/mg of extract), and with significant (p < 0.01) inhibitory contribution of decarboxylated-diferulic acid. Amongst the standards, caffeic acid presented the highest inhibition for both cholinesterases, 25.5 ± 0.2% for acetyl- and 52.3 ± 0.8% for butyryl-cholinesterase, respectively, whilst the blends insignificantly inhibited both cholinesterases. The results showed that polyphenol-rich BSG fractions have potentials as natural anti-cholinesterase agents.

Design, Synthesis and Biological Evaluation of New Cycloalkyl Fused Quinolines Tethered to Isatin Schiff Bases as Cholinesterase Inhibitors

Aims and Objective: Alzheimer’s disease is now a most prevalent neuro degenerative disease of central nervous system leading to dementia in elderly aged population. Numerous pathological changes have been associated in the progression of Alzheimer’s disease. One of such pathological hypothesis is declined cholinergic activity which eventually affects cognitive and memory deficits. Inhibition cholinesterases will apparently elevate acetyl choline levels which is benefactor on cognitive symptoms of the disease. This manuscript describes the new tacrine derivatives tethered to isatin Schiff bases through alkanoyl linker and screened for cholinesterase inhibitory activity. Materials and Methods: Tacrine and two more cycloalkyl ring fused quinolones were synthesized and converted to Ncycloalkyl fused quinoline chloroamides. Isatin Schiff bases were also synthesized by the reaction between isatin and substituted aromatic anilines and in subsequent reaction, isatin Schiff bases were reacted with cycloalkyl fused quinolones to afford anticipated compounds 10a-i, 11a-i and 12a-i. All the compounds have been screened for acetyl and butyryl cholinesterase inhibitory activity and in vivo behavioral studies. Binding interactions of the desired compounds have also been studied by docking them in active site of both cholinesterases. Results: Three compounds 12d, 12e and 12h with propionyl and butyroyl linker between amine and isatin Schiff base scaffold have shown potent acetyl and butyryl cholinesterase inhibitory activity. However most potent cholinesterase inhibitor was 13d with IC50 value of 0.71±0.004 and 1.08±0.02 μM against acetyl and butyryl cholinesterases respectively. The hepatotoxicity of potent compounds revealed that the tested compounds were less hepatotoxic than tacrine and also exhibited encouraging in vivo behavioral studies in test animals. Docking studies of all the molecules disclosed close hydrogen bond interactions within the binding site of both cholinesterases. Conclusion: New cycloalkyl fused quinolones tethered with alkoyl linker to isatin Schiff bases endowed significant and potent cholinesterase inhibitory activities. Few of the compounds have also exhibited lesser hepatotoxicity and all the synthesized compounds were good in behavioral studies. Molecular docking studies also indicated close interactions in active site of cholinesterases.