Search

Abstract: Viral infections range from self-limiting to more serious and fatal infections; therefore, some viral infections are of great public health concern worldwide, e.g., Hepatitis B virus, Hepatitis C virus, and HIV. Recently, the world faced a new infection due to the coronavirus, COVID-19, which was announced as a pandemic in early 2020. This virus infected more than 500 million people, killing around 6 million people worldwide. On the other hand, the increase in drug-resistant strains is also creating serious health problems. Thus, developing new selective antiviral agents with a different mode of action to fight against mutated and novel viruses is a primary goal of many researchers. Taking into account the role of heterocyclic compounds in drug discovery as a key structural component of most of the bioactive molecules; herein, we report an extensive review of the antiviral activity of five-membered heterocyclic compounds reported from 2015 to date. In this review, the antiviral activities of the agents containing the specified ring systems thiadiazoles, triazoles, oxadiazoles, and thiazoles are discussed.

Aims: Biological studies have shown that some condensed derivatives of pyrano[3,4- c]pyridines 6 exhibited pronounced biological activity. Considering these results, the principal aim of this work is to study the regiochemistry of the synthesis of pyrano[3,4-c]pyridines 6, to optimize the reaction conditions and thus to increase the previously observed low yields of pyrano[ 3,4-c]pyridines. Background: Within this research line, some of us, several years ago, developed a method for the preparation of 6-oxopyrano[3,4-c]pyridines 6 starting from 2,2-dimethyltetrahydro-4Hpyran- 4-one 1. In these studies, we separated and identified only the most expected reaction products 6-oxopyrano[3,4-c]pyridines 6. On the basis of this datum, we suggested that the enamines 2 and 3, reacting with acyl chlorides, were not acylated at C-3 and that 5-acylpyran-4- ones 4 were the only products of the reaction. We have justified this result by considering the steric effects exerted by the two methyl groups present in the pyran ring. Moreover, we did not identify the products at the second reaction center: that is, the isomeric compounds 7 and this result was justified considering the different reactivity of aliphatic and cyclic ketone groups. Objectives: The main objectives of this work were: • implementation of the reaction of 2,2-dimethyltetrahydro-4H-pyran-4-one 1 with morpholine; • acylation of the obtained enamines 2 and 3 with acyl chlorides under Stork conditions; • synthesis of pyranopyridines 6-8 based on β-diketones: 3-acylpyran-4-ones 4 and 5-acylpyran-4-ones 5; • confirmation of the structure of the obtained compounds. Methods: For the synthesis of pyrano[3,4-c]pyridines known methods were used. Thus, the reaction of starting 2,2- dimethyltetrahydro-4H-pyran-4-one 1 with morpholine in benzene led to the formation of isomeric enamines 2 and 3. After, they were acylated with acyl chlorides under Stork conditions with formation of two β -diketones: 3- acylpyran-4-ones 4 and 5-acylpyran-4-ones 5. Finally, in order to obtain the aimed pyrano[3,4-c]pyridines 6, the obtained β-dicarbonyl compounds 4 and 5 (as a mixture of isomers) were reacted with 2-cyanoacetamide in ethanol in the presence of diethylamine, according to the Knoevenagel condensation. The structure of the obtained compounds has been unambiguously confirmed by using a wide spectrum of physico-chemical methods (NMR, IR, Xray structural and elemental analysis) and, in the instance of compounds 7, also by an alternative synthesis. Results: Starting from the 2,2-dimethyltetrahydro-4H-pyran-4-one 1 a series of new and already known 6- oxopyrano[3,4-c]pyridines 6 were synthesized. As a result of the study of the regiochemistry in the synthesis of pyrano[3,4-c]pyridines, of the four possible isomer pyranopyridines 6-9, we have succeeded in identifying three of them (6-8). Thus, isomer pyranopyridines 7 and 8 were identified in the mixture with the main compounds 6. Moreover, isomeric pyrano[3,4-c]pyridines 8 were detected when alkyl groups are present in the starting compounds 4 and 5, while isomeric pyrano[4,3-b]pyridines 7 were detected in the case of the presence of aromatic groups. Unfortunately, we have not been able to isolate compounds 7 and 8 in the pure state from the reaction mixtures. At now, we have not been able to detect and identify isomeric pyrano[4,3-b]pyridines 9. On the whole, we have been able to better the effectiveness of the synthesis of pyrano[3,4-c]pyridines 6, increasing their yields by ≈ 5-15%. Conclusion: As a result of our investigation, we have found that the acylation reaction of enamines 2 and 3 and the cyclization reaction of β-diketones 4 and 5 are not regioselective. Therefore, we can state that enamines 2 and 3 can be acylated at both C-3 and C-5 with the formation of a mixture of 3-acylpyran-4-ones 4 and of 5-acylpyran-4-ones 5. Their condensation with 2-cyanoacetamide led to the formation of mixtures of regioisomeric pyranopyridines 6- 8. In conclusion, as a result of our present research, we can say that we have been able to increase the effectiveness of the synthesis of pyranopyridines, largely improving our previous results. Other: Now, we are working to look for the fourth isomeric pyrano[4,3-b]pyridines 9 by using the most modern and fine methods. Moreover, we hope that we shall be able to separate the mixtures of pyranopyridines 6-8: any way they can be used for further syntheses as they are.

Background.: Inflammation is a multifactorial process reflecting the response of the organism to various stimuli and is associated with a number of disorders such as arthritis, asthma and psoriasis, which require long-lasting or repeated treatment. Objective.: The aim of this paper is to evaluate the anti-inflammatory activity of previous synthesized thiazole-based chalcone derivatives. Methods: Chalcones were synthesized via Cliazen-Schmidt condensation1-(4-methyl-2- alkylamino)thiazol-5-yl) ethanone with a corresponding aromatic aldehyde. For the evaluation of possible anti-inflammatory activity, carrageenan mouse paw edema was used. Results.: Eight out of thirteen tested chalcones showed anti-inflammatory activity in a range of 51- 55%. Prediction of toxicity revealed that these compounds are not toxic. Conclusion.: In general, it can be concluded that these compounds can be used for further modifications in order to develop more active and safe agents.

Background:Thiazole derivates as well as chalcones, are very important scaffold for medicinal chemistry. Literature survey revealed that they possess wide spectrum of biological activities among which are anti-inflammatory and antimicrobial.Objectives:The current studies describe the synthesis and evaluation of antimicrobial activity of twenty eight novel thiazole-based chalcones.Methods:The designed compounds were synthesized using classical methods of organic synthesis. The in vivo evaluation of antimicrobial activity was performed by microdilution method.Results:All compounds have shown antibacterial properties better than that of ampicillin and in many cases better than streptomycin. As far as the antifungal activity is concerned, all compounds possess much higher activity than reference drugs bifonazole and ketoconazole. The most sensitive bacterial species was B. cereus (MIC 6.5-28.4 µmol × 10-2/mL and MBC 14.2-105.0 µmol × 10-2/mL) while the most resistant ones were L. monocytogenes (MIC 21.4-113.6 µmol × 10-2/mL) and E. coli (MIC 10.7- 113.6 µmol × 10-2/mL) and MBC at 42.7-358.6 µmol × 10-2/mL and 21.4-247.2 µmol × 10-2/mL, respectively. All the compounds exhibited antibacterial activity against the three resistant strains, MRSA, P. aeruginosa and E.coli. with MIC and MBC in the range of 0.65-11.00 µmol/mL × 10-2 and 1.30-16.50 µmol/mL × 10-2. Docking studies were performed.Conclusion:Twenty-eight novel thiazole-based chalcones were designed, synthesized and evaluated for antimicrobial activity. The results showed that these derivatives could be lead compounds in search of new potent antimicrobial agents. Docking studies indicated that DNA gyrase, GyrB and MurA inhibition may explain the antibacterial activity.

Background and Objective: Continuing our studies in the field of a new rearrangement in the 2,7- naphthyridine series, the synthesis and rearrangement of mono- 2 and di-amino derivatives 3 of 2,7- naphthyridine was carried out. Taking into account the wide range of pharmacological activities of pyrazole derivatives the synthesis of some 3-amino-1-(3,5-dimethyl-1H-pyrazol-1-yl)-2,7-naphthyridines 8 and of pyrazolo[3,4-c]-2,7-naphthyridine 12 was described. Methods: Compounds 2 were reacted with amines furnishing the relevant rearrangement products 4. Starting from the 7-benzyl-3-chloro-1-hydrazino-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile 6 and 5-hydrazino- 6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]-2,7-naphthyridin-1-amine 12 the 7-benzyl-3-chloro-1-(3,5-dimethyl-1Hpyrazol- 1-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile 7 and 3,5-dimethyl-1H-pyrazol-1-yl-9,11- dimethylpyrimido[1',2':1,5]pyrazolo[3,4-c]-2,7-naphthyridine 13 were synthesized, via the Knorr synthesis of pyrazoles. Results: The syntheses of 2-benzyl-6,8-diamino-3,4-dihydro-2,7-naphthyridin-1(2H)ones 4 deriving from the rearrangement of compounds 2 and/or 3 were performed. By reaction with benzylamine compound 2a or 3g gave the unexpected formation of N,7-dibenzyl-8-(benzylimino)-3-pyrrolidin-1-yl-5,6,7,8-tetrahydro-2,7- naphthyridin-1-amine 5: in fact, the rearrangement was followed by condensation between the C-1 carbonyl group of the 2,7-naphthyridine ring and the benzylamine. Starting from the 7-benzyl-3-chloro-1-(3,5-dimethyl- 1H-pyrazol-1-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile 7 the relevant 3-amino-7-benzyl-1-(3,5- dimethyl-1H-pyrazol-1-yl)-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitriles 8 were obtained. In harsh experimental conditions the nucleophilic substitution of the 1-pyrazolyl residue took place with formation of 7- benzyl-1,3-bis[(2-hydroxypropyl)amino]-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile 10. Moreover compound 7 reacted with hydrazine hydrate giving the pyrazolo[3,4-c]-2,7-naphthyridine 12, which, in turn furnished a new tetra-heterocyclic system: 3-benzyl-5-(3,5-dimethyl-1H-pyrazol-1-yl)-9,11-dimethyl-1,2,3,4- tetrahydropyrimido[1',2': 1,5]pyrazolo[3,4-c]-2,7-naphthyridine 13. Conclusion: Replacement of methyl group on piperidine ring of 2,7-naphthyridine system with the benzyl one led to new results. Reaction of compound 2a or 3g with benzylamine brought to an unexpected formation of N,7-dibenzyl-8-(benzylimino)-3-pyrrolidin-1-yl-5,6,7,8-tetrahydro-2,7-naphthyridin-1-amine 5. The reactivity of 7-benzyl-3-chloro-1-(3,5-dimethyl-1H-pyrazol-1-yl)-2,7-naphthyridine 7 with nucleophiles was investigated observing the unexpected substitution of the 1-pyrazolyl residue.