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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.

Herein we report the evaluation of the antimicrobial activity of some previously synthesized 3-(3,4-dihydroxyphenyl)glyceric acid in benzylated and in free 3,4 hydroxy groups in catechol moiety along with some caffeic and 3-(3,4-dihydroxyphenyl)glyceric acid amides using the microdilution method. The evaluation revealed that compounds showed in general moderate to low activity with MIC in range of 0.36-4.5 mg/mL. Compounds were also studied against three resistant bacteria strains MRSA (Methicillin-resistant

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.

In this manuscript, we describe the design, preparation, and studies of antimicrobial activity of a series of novel heteroarylated benzothiazoles. A molecular hybridization approach was used for the designing compounds. The in vitro evaluation exposed that these compounds showed moderate antibacterial activity. Compound 2j was found to be the most potent (MIC/MBC at 0.23–0.94 mg/mL and 0.47–1.88 mg/mL) On the other hand, compounds showed good antifungal activity (MIC/MFC at 0.06–0.47 and 0.11–0.94 mg/mL respectively) with 2d being the most active one. The docking studies revealed that inhibition of E. coli MurB and 14-lanosterol demethylase probably represent the mechanism of antibacterial and antifungal activities.

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.

The beginning of the end or the end of the beginning? After two years mastered by coronavirus disease 19 (COVID-19) pandemic, we are now witnessing a turnaround. The reduction of severe cases and deaths from COVID-19 led to increasing importance of a new disease called post-COVID syndrome. The term post-COVID is used to indicate permanency of symptoms in patients who have recovered from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Immune, antiviral, antimicrobial therapies, as well as ozone therapy have been used to treat COVID-19 disease. Vaccines have then become available and administered worldwide to prevent the insurgence of the disease. However, the pandemic is not over yet at all given the emergence of new omicron variants. New therapeutic strategies are urgently needed. In this view, great interest was found in nutraceutical products, including vitamins (C, D, and E), minerals (zinc), melatonin, probiotics, flavonoids (quercetin), and curcumin. This review summarizes the role of nutraceuticals in the prevention and/or treatment of COVID-19 disease and post-COVID syndrome.

Broad-spectrum antiviral agents that are effective against many viruses are difficult to develop, as the key molecules, as well as the biochemical pathways by which they cause infection, differ largely from one virus to another. This was more strongly highlighted by the COVID-19 pandemic, which found health systems all over the world largely unprepared and proved that the existing armamentarium of antiviral agents is not sufficient to address viral threats with pandemic potential. The clinical protocols for the treatment of COVID-19 are currently based on the use of inhibitors of the inflammatory cascade (dexamethasone, baricitinib), or inhibitors of the cytopathic effect of the virus (monoclonal antibodies, molnupiravir or nirmatrelvir/ritonavir), using different agents. There is a critical need for an expanded armamentarium of orally bioavailable small-molecular medicinal agents, including those that possess dual antiviral and anti-inflammatory (AAI) activity that would be readily available for the early treatment of mild to moderate COVID-19 in high-risk patients. A multidisciplinary approach that involves the use of in silico screening tools to identify potential drug targets of an emerging pathogen, as well as in vitro and in vivo models for the determination of a candidate drug’s efficacy and safety, are necessary for the rapid and successful development of antiviral agents with potentially dual AAI activity. Characterization of candidate AAI molecules with physiologically based pharmacokinetics (PBPK) modeling would provide critical data for the accurate dosing of new therapeutic agents against COVID-19. This review analyzes the dual mechanisms of AAI agents with potential anti-SARS-CoV-2 activity and discusses the principles of PBPK modeling as a conceptual guide to develop new pharmacological modalities for the treatment of COVID-19.

Despite the greatest achievement in the development of anti-inflammatory agents in the last two decades, the current clinical drugs suffer from a variety of complications in community settings and hospital. There is still an urgent need to design novel molecules with better safety profile and with different molecular targets from those in current clinical use. The aim of this research was to discover a series of benzothiazole-based thiazolidinones with lipoxygenase (LOX) inhibitory activity as a mechanism of anti-inflammatory action. Carrageenan-induced mouse foot paw oedema assay was carried out to determine the anti-inflammatory activity, while LOX inhibition was examined through the conversion of sodium linoleate to 13-hydroperoxylinoleic acid. Molecular docking studies were performed using AutoDock 4.2 software. The anti-inflammatory activity of the title compounds was determined in a range of 18.4%-69.57%, where compound #3 was found to be the most potent (69.57%) and also to be more active than the reference drug indomethacin (47%). Moreover, compound #3 showed the highest LOX inhibitory activity with IC

The Janus kinase (JAK) and epidermal growth factor receptor (EGFR) have been considered as potential targets for cancer therapy due to their role in regulating proliferation and survival of cancer cells. In the present study, the aromatic alkyl-amino analogs of thiazole-based chalcone were selected to experimentally and theoretically investigate their inhibitory activity against JAK2 and EGFR proteins as well as their anti-cancer effects on human cancer cell lines expressing JAK2 (TF1 and HEL) and EGFR (A549 and A431). In vitro cytotoxicity screening results demonstrated that the HEL erythroleukemia cell line was susceptible to compounds 11 and 12, whereas the A431 lung cancer cell line was vulnerable to compound 25. However, TF1 and A549 cells were not sensitive to our thiazole derivatives. From kinase inhibition assay results, compound 25 was found to be a dual inhibitor against JAK2 and EGFR, whereas compounds 11 and 12 selectively inhibited the JAK2 protein. According to the molecular docking analysis, compounds 11, 12 and 25 formed hydrogen bonds with the hinge region residues Lys857, Leu932 and Glu930 and hydrophobically came into contact with Leu983 at the catalytic site of JAK2, while compound 25 formed a hydrogen bond with Met769 at the hinge region, Lys721 near a glycine loop, and Asp831 at the activation loop of EGFR. Altogether, these potent thiazole derivatives, following Lipinski's rule of five, could likely be developed as a promising JAK2/EGFR targeted drug(s) for cancer therapy.

The synthesis of new cyclopenta[4',5']pyrido[3',2':4,5]furo[3,2-d]pyrimidin-7-amines have been carried out to study their antimicrobial activity. The biological tests evidenced that some of the synthesized compounds exhibit pronounced antimicrobial properties. A study of the structure–activity relationship revealed that the 3,5-dimethyl-1H-pyrazol-1-yl moiety linked to the carbon C-9 of the pyrimidine plays a decisive role in the manifestation of activity. The influence of 3,5-dimethyl-1H-pyrazol-1-yl group on the Dimroth rearrangement and azide-tetrazole equilibrium has also been examined.

A new effective method for the synthesis of imidazo[1,5-b]pyridazines derivatives (yields = 68–89%) by the interaction of 1,2-diamino-4-phenylimidazole with DMAD, in methanol and in the presence of a catalytic amount of acetic acid, is proposed. The course of reaction has been examined by classical organic methods, HPLC-MS analysis, and quantum-chemical calculations.

In this paper we describe an efficient method for the synthesis of new heterocyclic systems: furo[2,3

Major obstacles faced by the use of nonsteroidal anti-inflammatory drugs (NSAID) are their gastrointestinal toxicity induced by non-selective inhibition of both cyclooxygenases (COX) 1 and 2 and their cardiotoxicity associated with a certain class of COX-2 selective inhibitors. Recent studies have demonstrated that selective COX-1 and COX-2 inhibition generates compounds with no gastric damage. The aim of the current study is to develop novel anti-inflammatory agents with a better gastric profile. In our previous paper, we investigated the anti-inflammatory activity of 4-methylthiazole-based thiazolidinones. Thus, based on these observations, herein we report the evaluation of anti-inflammatory activity, drug action, ulcerogenicity and cytotoxicity of a series of 5-adamantylthiadiazole-based thiazolidinone derivatives. The in vivo anti-inflammatory activity revealed that the compounds possessed moderate to excellent anti-inflammatory activity. Four compounds 3, 4, 10 and 11 showed highest potency (62.0, 66.7, 55.8 and 60.0%, respectively), which was higher than the control drug indomethacin (47.0%). To determine their possible mode of action, the enzymatic assay was conducted against COX-1, COX-2 and LOX. The biological results demonstrated that these compounds are effective COX-1 inhibitors. Thus, the IC50 values of the three most active compounds 3, 4 and 14 as COX-1 inhibitors were 1.08, 1.12 and 9.62 μΜ, respectively, compared to ibuprofen (12.7 μΜ) and naproxen (40.10 μΜ) used as control drugs. Moreover, the ulcerogenic effect of the best compounds 3, 4 and 14 were evaluated and revealed that no gastric damage was observed. Furthermore, compounds were found to be nontoxic. A molecular modeling study provided molecular insight to rationalize the COX selectivity. In summary, we discovered a novel class of selective COX-1 inhibitors that could be effectively used as potential anti-inflammatory agents.

This is the first part of a Special Issue on enzymes and enzymes inhibitors and their applications in medicine and diagnosis [...]

Over the years, carbazoles have been largely studied for their numerous biological properties, including antibacterial, antimalarial, antioxidant, antidiabetic, neuroprotective, anticancer, and many more. Some of them have gained great interest for their anticancer activity in breast cancer due to their capability in inhibiting essential DNA-dependent enzymes, namely topoisomerases I and II. With this in mind, we studied the anticancer activity of a series of carbazole derivatives against two breast cancer cell lines, namely the triple negative MDA-MB-231 and MCF-7 cells. Compounds 3 and 4 were found to be the most active towards the MDA-MB-231 cell line without interfering with the normal counterpart. Using docking simulations, we assessed the ability of these carbazole derivatives to bind human topoisomerases I and II and actin. In vitro specific assays confirmed that the lead compounds selectively inhibited the human topoisomerase I and interfered with the normal organization of the actin system, triggering apoptosis as a final effect. Thus, compounds 3 and 4 are strong candidates for further drug development in multi-targeted therapy for the treatment of triple negative breast cancer, for which safe therapeutic regimens are not yet available.

This study reports the antimicrobial activities of the biopolymers poly[3-(3,4-dihydoxyphenyl)glyceric acid] (PDHPGA) and poly[2-methoxycarbonyl-3-(3,4-dihydroxyphenyl)oxirane] (PMDHPO), extracted from the six plants of Boraginaceae family: Symphytum asperum (SA), S. caucasicum (SC), S. gr and iflorum (SG), Anchusa italica (AI), Cynoglosum officinale (CO), and Borago officinalis (BO) collected in various parts of Georgia. The study revealed that the antibacterial activities were moderate, and biopolymers from only three plants showed activities against all tested bacteria. Biopolymers from CO stems as well as SC and AI did not show any activity except low activity against a resistant P. aeruginosa strain, which was the most resistant among all three resistant strains. On the other hand, the antifungal activity was better compared to the antibacterial activity. Biopolymers from BO stems exhibited the best activities with MIC/MFC at 0.37–1.00 mg/mL and 0.75–1.5 mg/L, respectively, followed by those from SG stems. Biopolymers from SC and AI roots showed antifungal activities against all six fungi, in contrast to the antibacterial activity, while biopolymers from CO stems and SA roots had activities against four fungi and one fungus, respectively. The sugar-based catechol-containing biopolymers from BO stems demonstrated the best activities among all tested biopolymers against T. viride, P. funiculosum, P. cyclpoium var verucosum, and C. albicans (MIC 0.37 mg/mL). In addition, biopolymers from SG stems were half as active against A. fumigatus and T. viride as ketoconazole. Biopolymers from all plant materials except for CO stems showed higher potency than ketoconazole against T. viride. For the first time, it was shown that all plant materials exhibited better activity against C. albicans, one of the most dreadful fungal species.

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) remain the most promising anti-AIDS agents that target the HIV-1 reverse transcriptase enzyme (RT). However, the efficiency of approved NNRTI drugs has decreased by the appearance of drug-resistant viruses and side effects upon long-term usage. Thus, there is an urgent need for developing new, potent NNRTIs with broad spectrum against HIV-1 virus and with improved properties. In this study, a series of thiazolidinone derivatives was designed based on a butterfly mimicking scaffold consisting of a substituted benzothiazolyl moiety connected with a substituted phenyl ring via a thiazolidinone moiety. The most promising derivatives were selected using molecular docking analysis and PASS prediction program, synthesized and evaluated for HIV-1 RT inhibition. Five out of fifteen tested compounds exhibited good inhibitory action. It was observed that the presence of Cl or CN substituents at the position 6 of the benzothiazole ring in combination with two fluoro atoms at the ortho-positions or a hydrogen acceptor substituent at the 4-position of the phenyl ring are favourable for the HIV RT inhibitory activity.

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.

Taking into account previously obtained biological results on some polyheterocyclic compounds (containing different heteroatoms) and in particular on several 8-amino-5-isopropyl-2,2-dimethyl-10-(methylthio)-1,4-dihydro-2H-pyrano[4’’,3’’:4’,5’]pyrido[3’,2’:4,5]thieno[3,2-d]pyrimidines Ia-v we have carried out the synthesis of twentyone 8-amino-5-isobutyl-2,2-dimethyl-10-(methylthio)-1,4-dihydro-2H-pyrano[4’’,3’’:4’,5’]pyrido[3’,2’:4,5]thieno[3,2-d]pyrimidines 6. Therefore we have slightly modified the structure of the previously studied I introducing at C-5 an isobutyl group instead of the previously examined isopropyl ones in order to see if this variation (changing a little the lipophilicity) will affect the biological activity. Furthermore thieno[3,2-d]pyrimidine-8-thione 7 and their S-alkylated 8 were synthesized. Finally by alkylation of 5-isobutyl-2,2-dimethyl-10-thioxo-1,4,10,11-tetrahydro-2H-pyrano[4'',3'':4',5']pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-8(9H)-one 3 with alkyl dichlorides (bifunctional reagents) we realized the cyclization of a thiazole or thiazine ring on the [b] side of the pyrimidine ring with formation of the new condensed pentaheterocyclic systems: pyrano[4'',3'':4',5']pyrido[3',2':4,5]thieno[3,2-d][1,3]thiazolo[3,2-a]pyrimidin-8-one 11 and pyrano[4''',3''':4'',5'']pyrido[3'',2'':4',5']thieno[3',2':4,5]pyrimido[2,1-b][1,3]thiazin-8-one 12. It was found that some of the synthesized compounds showed interesting antimicrobial activity (by agar diffusion method) against some gram-positive and gram-negative bacilli strains. On the basis of some our previous results we have carried out the synthesis of several new polyheterocyclic compounds with the aim of studying their biological activity. Notwithstanding predictions from in silico tests furnished negative results, we have examined their antimicrobial activity (by agar diffusion methods) observing that several compounds showed very interesting activity. Then we can say that they represent new chemical entities.

Sepsis is a life-threatening disease that affects millions of people worldwide. Microbial infections that lead to sepsis syndrome are associated with an increased production of inflammatory molecules. Aldose reductase has recently emerged as a molecular target that is involved in various inflammatory diseases, including sepsis. Herein, a series of previously synthesized benzothiazole-based thiazolidinones that exhibited strong antibacterial and antifungal activities has been evaluated for inhibition efficacy against aldose reductase and selectivity toward aldehyde reductase under in vitro conditions. The most promising inhibitor 5 was characterized with IC50 value of 3.99 μM and a moderate selectivity. Molecular docking simulations revealed the binding mode of compounds at the active site of human aldose reductase. Moreover, owning to the absence of an acidic pharmacophore, good membrane permeation of the novel aldose reductase inhibitors was predicted. Excellent “drug-likeness” was assessed for most of the compounds by applying the criteria of Lipinski’s “rule of five”.

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.

Background: Inflammation is a complex response to noxious stimuli promoted by the release of chemical mediators from the damaged cells. Metabolic products of arachidonic acid, produced by the action of cyclooxygenase and lipoxygenase, play important roles in this process. Several non-steroidal anti-inflammatory drugs act as cyclooxygenase inhibitors. However, almost all of them have undesired side effects. Methods: Prediction of the anti-inflammatory action of the compounds was performed using PASS Program. The anti-inflammatory activity was evaluated by the carrageenan paw edema test. COX and LOX inhibitory actions were tested using ovine COX-1, human recombinant COX-2 and soybean LOX-1, respectively. Docking analysis was performed using Autodock. Results: All designed derivatives had good prediction results according to PASS and were synthesized and experimentally evaluated. The compounds exhibited in vivo anti-inflammatory action with eleven being equal or better than indomethacin. Although, some of them had no or low inhibitory effect on COX-1/2 or LOX, certain compounds exhibited COX-1 inhibition much higher than naproxen and COX-2 inhibition, well explained by Docking analysis. Conclusions: A number of compounds with good anti-inflammatory action were obtained. Although, some exhibited remarkable COX inhibitory action this activity did not follow the anti-inflammatory results, indicating the implication of other mechanisms.

Objectives Both pyridine and pyrano derivatives have been previously shown to possess biologically relevant activity. In this study, we report the incorporation of these two scaffolds into one molecule. Methods The designed 3,3-dimethyl-6-oxopyrano[3,4-c]pyridines were synthesized by the acylation of enamine under Stork conditions followed by condensation of formed β-diketones with 2-cyanoacetamide. The structures of these compounds were confirmed by using a wide spectrum of physico-chemical methods. Their antiplatelet, anticoagulant and vasodilatory activity together with toxicity were evaluated. Key findings A series of 6-oxopyrano[3,4-c]pyridines 3a–j was obtained. Four of these compounds were reported for the first time. None of the tested compounds demonstrated anticoagulant effect but 8-methyl derivative (3a) was a potent antiplatelet compound with IC50 numerically twice as low as the clinically used acetylsalicylic acid. A series of further mechanistic tests showed that 3a interferes with calcium signaling. The compound is also not toxic and in addition possesses vasodilatory activity as well. Conclusions Compound 3a is a promising inhibitor of platelet aggregation, whose mechanism of action should be studied in detail.

Herein we report the design, synthesis, computational, and experimental evaluation of the antimicrobial activity of fourteen new 3-amino-5-(indol-3-yl) methylene-4-oxo-2-thioxothiazolidine derivatives. The structures were designed, and their antimicrobial activity and toxicity were predicted in silico. All synthesized compounds exhibited antibacterial activity against eight Gram-positive and Gram-negative bacteria. Their activity exceeded those of ampicillin and (for the majority of compounds) streptomycin. The most sensitive bacterium was S. aureus (American Type Culture Collection ATCC 6538), while L. monocytogenes (NCTC 7973) was the most resistant. The best antibacterial activity was observed for compound 5d (Z)-N-(5-((1H-indol-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)-4-hydroxybenzamide (Minimal inhibitory concentration, MIC at 37.9&ndash, 113.8 &mu, M, and Minimal bactericidal concentration MBC at 57.8&ndash, 118.3 &mu, M). Three most active compounds 5d, 5g, and 5k being evaluated against three resistant strains, Methicillin resistant Staphilococcus aureus (MRSA), P. aeruginosa, and E. coli, were more potent against MRSA than ampicillin (MIC at 248&ndash, 372 &mu, M, MBC at 372&ndash, 1240 &mu, M). At the same time, streptomycin (MIC at 43&ndash, 172 &mu, M, MBC at 86&ndash, 344 &mu, M) did not show bactericidal activity at all. The compound 5d was also more active than ampicillin towards resistant P. aeruginosa strain. Antifungal activity of all compounds exceeded those of the reference antifungal agents bifonazole (MIC at 480&ndash, 640 &mu, M, and MFC at 640&ndash, 800 &mu, M) and ketoconazole (MIC 285&ndash, 475 &mu, M and MFC 380&ndash, 950 &mu, M). The best activity was exhibited by compound 5g. The most sensitive fungal was T. viride (IAM 5061), while A. fumigatus (human isolate) was the most resistant. Low cytotoxicity against HEK-293 human embryonic kidney cell line and reasonable selectivity indices were shown for the most active compounds 5d, 5g, 5k, 7c using thiazolyl blue tetrazolium bromide MTT assay. The docking studies indicated a probable involvement of E. coli Mur B inhibition in the antibacterial action, while CYP51 inhibition is likely responsible for the antifungal activity of the tested compounds.

In this study, we report the synthesis and antimicrobial activity of some new disubstituted piperazines. Thus, 3-chlorocyclopenta[c]pyridines and 6-chloropyrano[3,4-c]pyridine 1 under mild reaction conditions with piperazine gave the 3(6)-piperazine-substituted cyclopenta[c]pyridines and pyrano[3,4-c]pyridine 2. Furthermore, the latter, by alkylation with 2-chloro-N-1,3-thiazol-2-ylacetamide, led to the formation of the target compounds. The evaluation of the antibacterial activity revealed that 3k was the most potent compound. The most sensitive bacterium was found to be Listeria monocytogenes, whereas Staphylococcus aureus was the most resistant one. Three compounds, 3d, 3g, and 3k, were tested also against the following resistant strains: methicillin-resistant S. aureus (MRSA), Escherichia coli, and Pseudomonas aeruginosa. All three compounds appeared to be more potent than ampicillin against MRSA. Moreover, compound 3d showed a better activity than the reference drug ampicillin against P. aeruginosa, whereas 3g was more efficient against E. coli. The best antifungal activity was observed again for compound 3k. The most resistant fungi appeared to be Aspergillus fumigatus, whereas Trichoderma viride seemed the most sensitive one toward the compounds tested. Molecular docking studies on E. coli MurB, as well as on Candida albicans CYP51 and dihydrofolate reductase, were used for the prediction of the mechanisms of the antibacterial and antifungal activities, confirming the experimental results.

Numerous studies have been published in recent years with acceptable quantitative structure-activity relationship (QSAR) modeling based on heterogeneous data. In many cases, the training sets for QSAR modeling were constructed from compounds tested by different biological assays, contradicting the opinion that QSAR modeling should be based on the data measured by a single protocol. We attempted to develop approaches that help to determine how heterogeneous data should be used for the creation of QSAR models on the basis of different sets of compounds tested by different experimental methods for the same target and the same endpoint. To this end, more than 100 QSAR models for the IC50 values of ligands interacting with cyclooxygenase 1,2 (COX) and seed lipoxygenase (LOX), obtained from ChEMBL database were created using the GUSAR software. The QSAR models were tested on the external set, including 26 new thiazolidinone derivatives, which were experimentally tested for COX-1,2/LOX inhibition. The IC50 values of the derivatives varied from 89 μM to 26 μM for LOX, from 200 μM to 0.018 μM for COX-1, and from 210 μM to 1 μM for COX-2. This study showed that the accuracy of the models is dependent on the distribution of IC50 values of low activity compounds in the training sets. In the most cases, QSAR models created based on the combined training sets had advantages in comparison with QSAR models, based on a single publication. We introduced a new method of combination of quantitative data from different experimental studies based on the data of reference compounds, which was called "scaling".

8-Hydrazino derivatives of pyrano[3,4-c]pyridines and derivatives of the new heterocyclic system 3-thioxopyrano[3,4-c][1,2,4]triazolo[4,3-a]pyridines on the basis of methanesulfonates of pyrano[3,4-c]pyridinium were synthesized by optimization of a previously used method. Derivatives of alkylsulfonyl pyrano[3,4-c][1,2,4]triazolo[4,3-a]pyridines were also synthesized. All compounds were evaluated for their neurotropic activity. Among all the compounds tested for anticonvulsant activity by pentylenetetrazole and maximal electric shock seizure (MES) tests, six compounds (5a, 5b, 5e, 5g, 5j, and 5p) appeared to be active. These compounds were also evaluated for their anxiolytic as well as antidepressant activities using “open field”, “elevated plus maze” (EPM), and “forced swimming” tests, respectively. It should be mentioned that compounds tested by the “rotating rod” method did not affect neuromuscular coordination. The most active compound appeared to be 5g in all tests. Docking studies of the most active compounds were performed on the GABA(A) receptor, SERT and 5-HT(1A) receptor.

Since the time of its appearance until present, COVID-19 has spread worldwide, with over 71 million confirmed cases and over 1.6 million deaths reported by the World Health Organization (WHO). In addition to the fact that cases of COVID-19 are increasing worldwide, the Delta and Omicron variants have also made the situation more challenging. Herein, we report the evaluation of several thiazole/thiadiazole/benzothiazole based thiazolidinone derivatives which were chosen from 112 designed derivatives by docking as potential molecules to inhibit the main protease of SARS-CoV-2. The contained experimental data revealed that among the fifteen compounds chosen, five compounds (k3, c1, n2, A2, A1) showed inhibitory activity with IC50 within the range of 0.01–34.4 μΜ. By assessing the cellular effects of these molecules, we observed that they also had the capacity to affect the cellular viability of human normal MRC-5 cells, albeit with a degree of variation. More specifically, k3 which is the most promising compound with the higher inhibitory capacity to SARS-CoV-2 protease (0.01 μΜ) affects in vitro cellular viability only by 57% at the concentration of 0.01 μM after 48 h in culture. Overall, these data provide evidence on the potential antiviral activity of these molecules to inhibit the main protease of SARS-CoV-2, a fact that sheds light on the chemical structure of the thiazole/thiadiazole/benzothiazole based thiazolidin-4-one derivatives as potential candidates for COVID-19 therapeutics.

Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the essential reaction of CO2 hydration in all living organisms, being actively involved in the regulation of a plethora of patho-/physiological conditions. A series of chromene-based sulfonamides were synthesized and tested as possible CA inhibitors. On the other hand, in microorganisms, the β- and γ- classes are expressed in addition to the α- class, showing substantial structural differences to the human isoforms. In this scenario, not only human but also bacterial CAs are of particular interest as new antibacterial agents with an alternative mechanism of action for fighting the emerging problem of extensive drug resistance afflicting most countries worldwide. Pyrazolo[4,3-c]pyridine sulfonamides were synthesized using methods of organic chemistry. Their inhibitory activity, assessed against the cytosolic human isoforms hCA I and hCA II, the transmembrane hCA IX and XII, and β- and γ-CAs from three different bacterial strains, was evaluated by a stopped-flow CO2 hydrase assay. Several of the investigated derivatives showed interesting inhibition activity towards the cytosolic associate isoforms hCA I and hCA II, as well as the 3β- and 3γ-CAs. Furthermore, computational procedures were used to investigate the binding mode of this class of compounds within the active site of hCA IX. Four compounds (1f, 1g, 1h and 1k) were more potent than AAZ against hCA I. Furthermore, compound 1f also showed better activity than AAZ against the hCA II isoform. Moreover, ten compounds out of eleven appeared to be very potent against the γ-CA from E.coli, with a Ki much lower than that of the reference drug. Most of the compounds showed better activity than AAZ against hCA I as well as the γ-CA from E.coli and the β-CA from Burkholderia pseudomallei (BpsCAβ). Compounds 1f and 1k showed a good selectivity index against hCA I and hCA XII, while 1b was selective against all 3β-CA isoforms from E.coli, BpsCA, and VhCA and all 3γ-CA isoforms from E.coli, BpsCA and PgiCA.

Background: Infectious diseases represent a significant global strain on public health security and impact on socio-economic stability all over the world. The increasing resistance to the current antimicrobial treatment has resulted in the crucial need for the discovery and development of novel entities for the infectious treatment with different modes of action that could target both sensitive and resistant strains. Methods: Compounds were synthesized using the classical organic chemistry methods. Prediction of biological activity spectra was carried out using PASS and PASS-based web applications. Pharmacophore modeling in LigandScout software was used for quantitative modeling of the antibacterial activity. Antimicrobial activity was evaluated using the microdilution method. AutoDock 4.2® software was used to elucidate probable bacterial and fungal molecular targets of the studied compounds. Results: All compounds exhibited better antibacterial potency than ampicillin against all bacteria tested. Three compounds were tested against resistant strains MRSA, P. aeruginosa and E. coli and were found to be more potent than MRSA than reference drugs. All compounds demonstrated a higher degree of antifungal activity than the reference drugs bifonazole (6–17-fold) and ketoconazole (13–52-fold). Three of the most active compounds could be considered for further development of the new, more potent antimicrobial agents. Conclusion: Compounds 5b (Z)-3-(3-hydroxyphenyl)-5-((1-methyl-1H-indol-3-yl)methylene)-2-thioxothiazolidin-4-one and 5g (Z)-3-[5-(1H-Indol-3-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl]-benzoic acid as well as 5h (Z)-3-(5-((5-methoxy-1H-indol-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)benzoic acid can be considered as lead compounds for further development of more potent and safe antibacterial and antifungal agents.

Docking analysis was used to predict the effectiveness of adamantanyl insertion in improving cycloxygenase/lipoxygenase (COX/LOX) inhibitory action of previously tested 2-thiazolylimino-5-arylidene-4-thiazolidinones. The crystal structure data of human 5-LOX (3O8Y), ovine COX-1 (1EQH) and mouse COX-2 (3ln1) were used for docking analysis. All docking calculations were carried out using AutoDock 4.2 software. Following prediction results, 11 adamantanyl derivatives were synthesized and evaluated for biological action. Prediction evaluations correlated well with experimental biological results. Comparison of the novel adamantanyl derivatives with the 2-thiazolylimino-5-arylidene-4-thiazolidinones previously tested showed that insertion of the adamantanyl group led to the production of more potent COX-1 inhibitors, as well as LOX inhibitors (increased activity from 200% to 560%). Five compounds out of the 11 exhibited better activity than naproxen; while nine out of 11 showed better activity than NDGA and seven compounds possessed better anti-inflammatory activity than indomethacin.

A new thiazole-containing multidentate ligand 2-((2-phenylthiazol-4-yl)methylthio)ethanamine, L, was synthesized and used to prepare new complexes of the formula PdIILCl2 (Pd–L), CuIIL2Cl2 (Cu–L) and fac-[Re/99mTcI(CO)3(L)]+ (Re/99mTc–L). The ligand L and the metal complexes were characterized spectroscopically. Furthermore, the structures of Re–L and Cu–L were elucidated by X-ray crystallography. Ligand L acts as a bidentate (Nth, S) chelator in Pd–L, as a bidentate (N, S) chelator in Cu–L and as a tridentate (Nth, S, N) chelator in Re–L. The radiotracer 99mTc–L was synthesized in high yield and characterised by HPLC comparison with the Re–L analog. The synthesized compounds were evaluated for their anti-inflammatory and cytotoxic properties. The compounds exhibited low anti-inflammatory activity with Pd–L showing the highest activity among them. The cytotoxic activity of the ligand and the complexes against several human cancer cell lines (cervical adenocarcinoma HeLa, colorectal adenocarcinoma LS-174T, lung adenocarcinoma A549, breast adenocarcinoma MDA-MB-231 and normal human lung fibroblast cell line MRC-5) was examined using the MTT assay. The complex Cu–L exhibited the highest cytotoxicity and the complex Pd–L showed the best tumor selectivity. The changes in the cell cycle phase distribution were determined by flow cytometry and it was found that ligand L shows the highest apoptotic activity. The biodistribution studies of 99mTc–L in mice showed fast tissue clearance. Of all the thiazole-containing compounds, the palladium complex appears to be more promising for future efforts.

Pharmacological effects of biologically active “small molecules” can be improved by their targeted modification, which affects drug delivery and interaction with tumor cells and microorganisms. We aimed to evaluate anticancer and antimicrobial activity of lipid-like choline derivatives modified via simultaneous introduction of tetrahydro(iso)quinoline based pharmacophore system at nitrogen atom and long chain alkyl substituent at oxygen atom. Target compounds were synthesized under phase-transfer catalysis conditions followed by quaternization, and evaluated for cytotoxicity and NO-generation ability on HT-1080 and MG-22A tumor cell lines and NIH 3T3 normal mouse fibroblasts, and screened for antimicrobial activity against gram-positive (Staphylococcus aureus and Bacillus cereus) and gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa and Proteus mirabilis) and fungi (Candida albicans and Aspergillus niger). Inhibitory action of active compounds towards E. coli DNA gyrase was investigated. Target compounds exhibit high selective cytotoxicity (LC50 < 1 μg/mL) and NO-induction ability, and reveal strong antimicrobial activity with MIC and MBC/MFC values of 0.5–32 μg/mL, predominantly vs. gram-positive bacteria and fungi. Tested substances displayed inhibitory effect towards E. coli DNA gyrase, though less than ciprofloxacin. Tetrahydroisoquinoline derivatives and compounds possessing substituents with chain length of 10 and 11 carbon atoms have highest indices of activities. Lipid-like N-heterocyclic choline analogues based on 1,2,3,4-tetrahydro(iso)quinoline scaffold, possessing very high cytotoxicity with attendant strong antimicrobial activity are the leads for developing effective dual action therapeutics.

Background: From the literature it is known that many derivatives of fused thienopyrimidines and furopyrimidines possess broad spectrum of biological activity. Objectives: The current studies describe the synthesis and evaluation of antimicrobial activity of some new N-1,3-thiazol-2-ylacetamides of pyrido[3',2':4,5]furo(thieno)[3,2-d]pyrimidines. Methods: By cyclocondensation of ethyl 1-aminofuro(thieno)[2,3-b]pyridine-2-carboxylates 1with formamide were converted to the pyrido[3',2':4,5]furo(thieno)[3,2-d]pyrimidin-7(8)-ones 2.Alkylation of compound 2 with 2-chloro-N-1,3-thiazol-2-ylacetamide led to the aimed N-1,3-thiazol-2-ylaceta-mides of pyrido[3',2':4,5]furo(thieno)[3,2-d]pyrimidines 3. Starting from compound 2 the relevant S-alkylated derivatives of pyrido[3',2':4,5]furo(thieno)[3,2-d]pyrimidines 6 were also synthesized. Results: All the compounds showed antibacterial activity to non-resistant strains. Compounds 3a-3m showed antibacterial activity with MIC/MBC at 0.08-2.31 mg/mL/0.11-3.75 mg/mL .The two most active compounds, 3j and 6b, appeared to be more active towards MRSA than the reference drugs. Half of the tested compounds appeared to be equipotent/more potent than ketoconazole and more potent than bifonazole. The docking analysis provided useful information about the interactions occurring between the tested compounds and the different enzymes. Conclusion: Gram-negative and Gram-positive bacteria and fungi showed different response towards tested compounds, indicating that different substituents may lead to different modes of action or that the metabolism of some bacteria/fungi was better able to overcome the effect of the compounds or adapt to it.