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Introduction Coronavirus is causing health, economic, and social crisis all over the world. If it is not stopped soon in this way, otherwise it is feared that it will kill tens of thousands of people and degrade all humanity to a severe and prolonged recession. For the time being, the war in Covid 19 is mainly conducted through an effort to isolate people and prevent further adherence and by providing supportive care (especially the provision of fluids and oxygen) to those who have become ill and have respiratory distress. It is noteworthy: the infectious agents that can cause severe symptoms of the disease are mainly elderly and patients suffering from background diseases such as diabetes, cardiovascular diseases. For example, are high blood pressure and respiratory diseases such as asthma and Chronic Obstructive Pulmonary Disease (COPD). However, reports of mortality also obtained in young patients who were without risk factors and no background disease. At the same time, there is a widespread effort in the world to develop both a vaccine for the disease and to find drugs that will cure patients. The effort in the field of medicine is dealing with mainly two: an effort to develop new drugs for the disease and an attempt to test existing drugs that may also be effective in the treatment of Corona-illness [1]. In the context of drugs, the public raises other questions: Can the drug treatment that many people receive for other non-corona problems aggravate the c Covid 19? Are there any particular recommendations for patients who consume medication regularly? To date, there is no effective anti-coronary drug treatment, but the efficacy of existing drugs - some on the shelf - that are being used to treat other diseases is being investigated. Information on the efficacy of these drugs for the treatment of Covid 19 comes mainly from laboratory studies, but also from human clinical studies. People with pre-existing heart disease are more at risk for severe cardiovascular and respiratory complications from COVID-19. Similarly, research has shown that influenza virus infection poses a more serious threat to people with heart disease than those without heart problems. Studies have also shown that respiratory infections like the flu can actually trigger heart attacks. People with previously undiagnosed heart disease may present with quiet heart symptoms that were previously not obscured by the viral infection. In people with preexisting cardiovascular obstruction, infection, fever, and inflammation can undermine the stability of asymptomatic lipid plaque that previously existed in the heart vessels. Heat and inflammation also make the blood more prone to blood clotting, interfering with the body’s ability to dissolve blood clots - a one-two punch similar to gasoline injection on the coals of the wind [2]. Health officials from WHO have noted that Gilead’s remdesivir has demonstrated efficacy in treating the coronavirus infection.Health officials from WHO have noted that Gilead’s remdesivir has demonstrated efficacy in treating the coronavirus infection. Remdesivir is a broad spectrum antiviral drug originally intended for Ebola. Researchers have found that remdesivir is most effective in fighting the new coronavirus. This treatment has not yet been approved in humans, but two clinical trials of this drug have been implemented in China. One clinical trial was also recently approved by the FDA in the United States.Chloroquine. WASHINGTON - The US is fast-tracking the anti-malarial drug chloroquine for use as a treatment against the new coronavirus, US So said President Donald Trump on Thursday. Trump told reporters that “we can get this drug almost immediate, and that’s where the FDA [Food and Drug Administration] was so big”[3]. Doctors can also use a number of different treatments to limit the immune system’s response to viruses, such as fever and inflammation, which can sometimes cause more harm to the patient than the virus itself. Anti-inflammatory drugs such as corticosteroidsand chloroquine are most commonly used to reduce these symptoms. Chloroquine, a widely-used anti-malarial and autoimmune disease drug, has recently been reported as a potential broad spectrum antiviral drug. Chloroquine is known to block virus infection by increasing endosomal pH required for virus/ cell fusion, as well as interfering with the glycosylation of cellular receptors of SARS-CoV [4-7]. “Chloroquine, a relatively safe, effective, and inexpensive drug used to treat many human diseases, including malaria, embiosis, and human immunodeficiency virus, is effective in inhibiting infection and spread of SARS CoV in cell culture. Post-infection offers possible preventative and therapeutic use.” Chloroquine is a drug used to fight malaria and autoimmune diseases. It has been in use for over 70 years as a source material and is considered to be safe. Researchers have found that this drug is effective in fighting the SARS-CoV-2 virus in in vitro studies. At least 10 close-source clinical studies are currently examining the potential use of chloroquine as an option to fight the new coronavirus (Figure 1).

Penetration of the blood brain barrier (BBB) by appropriate fluorescent probes remains a challenge in optical imaging and diagnostics. We designed, synthesized and observed the in vivo BBB penetration of a LASER syn-bimane probe. Results demonstrate that the Aib transporter unit in our probe may lead a fluorescent bimanyl moiety across the BBB.

We synthesized new broad spectrum antibacterial cationic peptidomimetics centered on a hydrophobic 1,4-dihydropyridine (1,4-DHP) scaffold. The synthesis involves the preparation of the scaffold in a three step Hantzsch reaction followed by simultaneous coupling of the 1,4-DHP scaffold to two dipeptides bearing cationic side chains. The synthesized peptidomimetics were found to have no measurable toxic hemolytic effect against mammalian red blood cells. The compounds were found to have antibacterial activity against Gram-(−) and Gram-(+) bacteria with MICs in the range of 35–100 μg/mL. These cationic antimicrobial peptidomimetics will lead to more effective antibacterial drug candidates based on a synthetically accessible scaffold.

Peptide nucleic acid (PNA) is a DNA analog able to form hybridization complexes with complementary DNA or RNA strands. Many PNAs have been described in recent years, particularly chiral PNA analogs. Chiral heteronucleotide ONA (Orn backbone PNA) is an important tool in the antisensing field, but was not been fully explored yet. In the present work, we performed studies toward the synthesis of chiral heteronucleotide ONA sequences by utilizing a Fmoc/Boc-based submonomer approach on solid support. The desired oligomers with different nucleic content and length were obtained in very good yields and high purity. Specific binding to the complimentary ssDNA oligomers was demonstrated.

Antimicrobial peptides (AMPs) appear to be good candidates for the development of new antibiotic drugs. We describe here the synthesis of peptidomimetic compounds that are based on a benzodiazepine scaffold flanked with positively charged and hydrophobic amino acids. These compounds mimic the essential properties of cationic AMPs. The new design possesses the benzodiazepine scaffold that is comprised of two glycine amino acids and which confers flexibility and aromatic hydrophobic 'back', and two arms used for further synthesis on solid phase for incorporation of charged and hydrophobic amino acids. This approach allowed us a better understanding of the influence of these features on the antimicrobial activity and selectivity. A novel compound was discovered which has MICs of 12.5 µg/ml against Staphylococcus aureus and 25 µg/ml against Escherichia coli, similar to the well-known antimicrobial peptide MSI-78. In contrast to MSI-78, the above mentioned compound has lower lytic effect against mammalian red blood cells. These peptidomimetic compounds will pave the way for future design of potent synthetic mimics of AMPs for therapeutic and biomedical applications.

The synthesis of dimethyl 2-acetoxy-2-(2,4-diiodo-5-aminophenyl)ethylphosphonate and dimethyl 2-acetoxy-2-(2,4,6-triiodo-3,5-diaminophenyl)ethylphosphonate is described. Several amido and peptidic derivatives of these two compounds were prepared. These products are composed of a combination of structural/functional moieties which pave the way for their potential application as non-ionic selective X-ray contrast agents.

Highly active lipase and protease complexes were prepared by non-covalent modification with stearic acid. The protein content and yield of the modified enzyme complexes depended on the enzymes' source. The increase in the transesterification activity of the modified enzymes was 15 fold for Candida rugosa lipase and porcine pancreatic lipase, with preservation of the enantioselectivity. Pseudomonas sp. lipase which showed no activity in its crude form, exhibited an activity of 38 μmol/h·mg protein in the modified form. © Rapid Science Ltd. 1998

This article presents a new method for topological analysis of molecular surfaces. Explicit representation of the van der Waals interaction according to the Lennard-Jones potential enabled determination of the function of the maximum radius of a hypothetical atomic probe in any location, r, inside the host's domain. The size of the spatial gradient of the maximal probe's volume (named the ξ value) at that location was found to be a good descriptor of the local shape of the host. Consequently, mapping of the host domain according to the ξ value could be used as a quantitative tool for localization of potent local binding sites. The proposed method is illustrated by mapping an organic host (calix[4]arene) as well as an enzyme (HIV-aspartic protease). Analysis of the calix[4]arene derivative revealed that the proposed method reproduces immediately the known binding site of conic calix[4]arenes. The second test case demonstrated how the catalytic site of the enzyme could be disassembled into many local binding sites. Some of these sites, located according to the proposed method, were found to follow the shape of a known inhibitor of the enzyme in a complementary manner. © 1995 John Wiley & Sons, Inc.

Nitrones 2a , 2b obtained from the aldehydes 1a , 1b , are used for the syntheses of the N-ethoxy iminium salts 4a and 4b . In the following procedure 4a and 4b react to several esters of phosphinic acids 6a - 6d .

Syntheses of α-Aminophosphonic Acids from N-Ethoxyiminium Salts, II Nitrones 2 obtained from aldehydes 1 are used for the synthesis of N-ethoxyiminium salts 3. These react with several esters of hydrogen phosphite 4 to give the N-methyl α-amino phosphonic esters 5 to 13. The N-benzyl α-amino phosphonic esters 24 and 25 can be obtained by the same procedure. Hydrogenolysis and ester hydrolysis afford the α-amino phosphonic acids 14 as well as 26 and 27, respectively.

The oxoiminium salts 4a, b, and 8 obtained by alkylation with Et3OBF4 of the aldonitrones 3a, b, and 7 react with diphenyl hydrogen phosphite to give the N-alkoxy α-amino phosphonic esters 6 and 9a, b. Similarly, the cyclic imine oxides 10a, b and the cyclic oxime ethers 14a, b afford the α-branched N-alkoxy α-amino phosphonic esters 12a, b and 16a, b, respectively. Hydrogenolysis and ester hydrolysis affords the α-methyl α-amino phosphonic acid hydrochlorides 13a, b and 17a, b.

For synthetic purposes, the polyether-based secondary alcohols 7 and 8 were prepared from acetone O-methyloxime (1). This applies the (Z) effect for the geometry-directed alkylation sequence, recovery of the keto group and reduction. In contrast to 11, α-phenylthio-substituted O-alkyloxime 26 was found to be unsuitable as starting material for such synthesis. The strong effect of bivalent sulfur in the α-position shadows the (Z) effect and permits only lithiation next to the sulfur atom.

The synthesis of optically pure chloromethyl (―)-menthyl ether (2b) and its use in the synthesis of di- (―)-menthyl acetal (―)-menthyl (+)-menthyl acetals are described. The diastereomeric mixed acetals 7a, b and 8a, b are easily obtainable from the nitrones 5 and 6, KCN and 2b. The mixtures of diastereomers are separated into the pure components 7a, 7b and 8a, 8b by simple silica gel column chromatography. Hydrolysis of these products (H 2 O 2 /Na 2 CO 3 , ultrasound) followed by N-O cleavage affords the heterocyclic α-methyl-α-amino amides 11a, 11b and 12a, 12b. These are subsequently hydrolyzed to give the corresponding α-methyl-α-amino acids with S and R configuration, respectively

Reaction of the dilithium salts of the dioxime diethers 1 gives the polyoxime-based macrocyclic systems 2–4. Temperature and lithium effects indicate that mixed aggregates play an important role in the formation of these heterocyclic systems by oxidative coupling. An X-ray structure analysis of 3f has been carried out showing that the thermodynamically unfavored Z configuration is a characteristic feature of this reaction product.

Lithiation of 5,6-dihydro-3-methyl-4H-1,2-oxazine (4) in an unpolar solvent system (hexane/THF) at −65°C followed by reaction with Cl2,Br2, or I2 affords cleanly and stereoselectively 6 (RS,RS) of which an X-ray structure analysis is described. In contrast, attempts to couple the halogenated 1,2-oxazine derivative 5c have given, under various reaction conditions, equal amouts of 6 and 8 (meso). A mechanism of this reaction is discussed.

Oxime ethers 1 react with ammonia and primary amines to give α-amino oxime ethers. The reaction of α-bromo oxime ethers with sodium azide affords α-azido oxime ethers. Hydrogenolysis of the azido compounds using 5% palladium on calcium carbonate as catalyst yields the α-amino oxime ethers. The reaction of α-azido oxime ethers with lithium aluminum hydride gives 1,2-ethanediamine derivatives. The reaction of azido oxime ether 13 with LiAlH4, and subsequently the reaction of the resulting mixture of the diamines 14 and 15 with phosgene, preferably gives cis-4-pentyl-5-methyl-2-imidazolidone (16) indicating that the reduction of 13 proceeds in a stereoselective manner to furnish mainly the syn-1,2-ethanediamine 15.

Reaction of the lithium salts of oxime ethers 4a–c with methanesulfonyl azide gives the α-diazo oxime ethers 5a–c. These novel compounds are stable up to 90°C, however, they decompose thermally in refluxing CCl4 and with PdCl2 catalysis to yield the ethylene diketone bis(O-methoxyloxime) derivatives 6a–c in yields of 85–91%. The preparation and characteristic spectral features of 5a–c are described.

The reaction of alkyl hydroxamates 2 with (C2H5)3O · BF4 in CH2Cl2 affords N-alkoxyimidates 3. The direct alkylation of hydroxamic acids 1 with 1,2-dibromoethane gives the 5,6-dihydro-1,4,2-dioxazine derivatives 4. The reactions of the acyclic imidates 3 as well as the cyclic N-alkoxyimidates 4 with N-bromosuccinimide in CCl4 produces the α-bromoimidates 5a–d and 6a–d. The α-bromine atom in the bromides 5b, d and 6a, b, d can be displaced by fluorine and azido substituents to yield the α-fluoro-N-alkoxyimidates 7b, d and 10a, b, d and the α-azido compounds 8b, d and 11a, b, d, respectively. The reduction of the azides 8b, d and 11a, b, d affords the α-aminoimidates 9b, d and 12ab, d, respectively. The reaction of the bromides 6a–d with benzene derivatives 14a–d in the presence of AgBF4 affords the aromatic substitution products 15a–d. Acid-catalyzed hydrolysis of 15a, c gives the arylsubstituted carboxylic acids 16 and 17.

The diselenacyclodecane ring in the title compound, C 12 H 20 N 4 O 4 Se 2 , adopts a twist-twist-boat conformation with regular trans positions of the oxime groups. In this conformation, the intramolecular spatial interaction of the oxime fragments decreases to a minimum. This molecule is an E,E,E,E isomer with regard to the configuration of the oxime groups

The synthesis of 2-(Aminophenyl)-2-hydroxyethylphosphonates rac-4a-c is based on the formation of a hydroxyl function via addition of the lithium salt of dimethyl methylphosphonate (2) to aldehydes 1a-c. The amino function in rac- 4a-c is obtained by catalytic reduction of the nitro group in 3 at low pressure. The incorporation of the aminophosphonates rac-4a-c in short peptides, enables the formation of potential bioactive materials 12–14.

Oxime ethers 1 react with ammonia and primary amines to give α-amino oxime ethers. The reaction of α-bromo oxime ethers with sodium azide affords α-azido oxime ethers. Hydrogenolysis of the azido compounds using 5% palladium on calcium carbonate as catalyst yields the α-amino oxime ethers. The reaction of α-azido oxime ethers with lithium aluminum hydride gives 1,2-ethanediamine derivatives. The reaction of azido oxime ether 13 with LiAlH4, and subsequently the reaction of the resulting mixture of the diamines 14 and 15 with phosgene, preferably gives cis-4-pentyl-5-methyl-2-imidazolidone (16) indicating that the reduction of 13 proceeds in a stereoselective manner to furnish mainly the syn-1,2-ethanediamine 15.

The reaction of alkyl hydroxamates 2 with (C2H5)3O · BF4 in CH2Cl2 affords N-alkoxyimidates 3. The direct alkylation of hydroxamic acids 1 with 1,2-dibromoethane gives the 5,6-dihydro-1,4,2-dioxazine derivatives 4. The reactions of the acyclic imidates 3 as well as the cyclic N-alkoxyimidates 4 with N-bromosuccinimide in CCl4 produces the α-bromoimidates 5a–d and 6a–d. The α-bromine atom in the bromides 5b, d and 6a, b, d can be displaced by fluorine and azido substituents to yield the α-fluoro-N-alkoxyimidates 7b, d and 10a, b, d and the α-azido compounds 8b, d and 11a, b, d, respectively. The reduction of the azides 8b, d and 11a, b, d affords the α-aminoimidates 9b, d and 12ab, d, respectively. The reaction of the bromides 6a–d with benzene derivatives 14a–d in the presence of AgBF4 affords the aromatic substitution products 15a–d. Acid-catalyzed hydrolysis of 15a, c gives the arylsubstituted carboxylic acids 16 and 17.

Reaction of the dilithium salts of the dioxime diethers 1 gives the polyoxime-based macrocyclic systems 2–4. Temperature and lithium effects indicate that mixed aggregates play an important role in the formation of these heterocyclic systems by oxidative coupling. An X-ray structure analysis of 3f has been carried out showing that the thermodynamically unfavored Z configuration is a characteristic feature of this reaction product.

Stable carbocations (A), carbanions (B) and free radicals (C) are expected to result from 3-substituted-5, 6-dihydro-1,4,2-dioxazine 1 or their 3- (1-bromoalkyl) derivative 2, due to the presence of a CN double bond, adjacent to the active methylene group. However, experimental data indicate that while A and C could be obtained, B was apparently too unstable to act as an intermediate in alkylations. A theoretical study of the structures and stabilities of A-C resulting from 1 and 2 (R = CH3), in the framework of a semiempirical all-valence electron molecular orbital approximation (AMI) is described. The results obtained indicate that A and C can be stabilized by delocalization and accommodation of the positive charge and unpaired electron respectively, by conjugation, hyperconjugation and field effects. Although B has a non-uniform distribution of the charge due to a less planar shape, it should be stabilized by delocalization. Calculated energies of reaction (Er) for the formation of B, and deprotonation enthalpy (DPE) of 1 (R = CH3) in comparison with the deprotonation of 3-methyl-4H-5,6-dihydrooxazine (6), a structurally related compound proven to lead to carbanions (B′ and B″), could not explain the failure to perform carbanion-mediated alkylations.

Lithiation of 5,6-dihydro-3-methyl-4H-1,2-oxazine (4) in an unpolar solvent system (hexane/THF) at −65°C followed by reaction with Cl2,Br2, or I2 affords cleanly and stereoselectively 6 (RS,RS) of which an X-ray structure analysis is described. In contrast, attempts to couple the halogenated 1,2-oxazine derivative 5c have given, under various reaction conditions, equal amouts of 6 and 8 (meso). A mechanism of this reaction is discussed.

For synthetic purposes, the polyether-based secondary alcohols 7 and 8 were prepared from acetone O-methyloxime (1). This applies the (Z) effect for the geometry-directed alkylation sequence, recovery of the keto group and reduction. In contrast to 11, α-phenylthio-substituted O-alkyloxime 26 was found to be unsuitable as starting material for such synthesis. The strong effect of bivalent sulfur in the α-position shadows the (Z) effect and permits only lithiation next to the sulfur atom.

The oxoiminium salts 4a, b, and 8 obtained by alkylation with Et3OBF4 of the aldonitrones 3a, b, and 7 react with diphenyl hydrogen phosphite to give the N-alkoxy α-amino phosphonic esters 6 and 9a, b. Similarly, the cyclic imine oxides 10a, b and the cyclic oxime ethers 14a, b afford the α-branched N-alkoxy α-amino phosphonic esters 12a, b and 16a, b, respectively. Hydrogenolysis and ester hydrolysis affords the α-methyl α-amino phosphonic acid hydrochlorides 13a, b and 17a, b.

The diselenacyclodecane ring in the title compound, C 12 H 20 N 4 O 4 Se 2 , adopts a twist-twist-boat conformation with regular trans positions of the oxime groups. In this conformation, the intramolecular spatial interaction of the oxime fragments decreases to a minimum. This molecule is an E,E,E,E isomer with regard to the configuration of the oxime groups

The synthesis of dimethyl 2-acetoxy-2-(2,4-diiodo-5-aminophenyl)ethylphosphonate and dimethyl 2-acetoxy-2-(2,4,6-triiodo-3,5-diaminophenyl)ethylphosphonate is described. Several amido and peptidic derivatives of these two compounds were prepared. These products are composed of a combination of structural/functional moieties which pave the way for their potential application as non-ionic selective X-ray contrast agents.

Regiocontrolled deprotonation (e. g. lithiation) of acetone O-methyloxime (1), 5,6-dihydro-3-methyl-4H-1,2-oxazine (9a) and 4,5-dihydro-3-methylisoxazole (9b) is achieved within 1 minute at −65°C in hexane/THF. The lithiated compounds react very fast at low temperature (−65°C) with diidomethane to give mainly the corresponding α-iodomethylene oxime ethers 6 and 11a, b. A radical mechanism of this reaction is discussed.

Reaction of the lithium salts of oxime ethers 4a–c with methanesulfonyl azide gives the α-diazo oxime ethers 5a–c. These novel compounds are stable up to 90°C, however, they decompose thermally in refluxing CCl4 and with PdCl2 catalysis to yield the ethylene diketone bis(O-methoxyloxime) derivatives 6a–c in yields of 85–91%. The preparation and characteristic spectral features of 5a–c are described.

The Ag+ induced aromatic substitution reactions of 3-(1-bromomethyl)-5,6-dihydro-1,4,2-dioxazine derivatives via an α-acyl cation equivalent are described.

Several mono- and di-O-alkyloximes have been regioselectively transformed to the syn α-lithio derivatives by treatment with n-butyllithium. The control of oxime ether geometry served to control regioselectivity in α-lithiation and subsequent carbon-carbon (alkylation, oxidative coupling) and carbon-halogen bond formation reactions. The geometry-directed α-lithiation-dimerization sequence was used for the synthesis of large ring compounds.