5-Membered Heterocyclic Compounds as Antiviral Agents.

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.

Identification of Novel Cyclooxygenase-1 Selective Inhibitors of Thiadiazole-Based Scaffold as Potent Anti-Inflammatory Agents with Safety Gastric and Cytotoxic Profile.

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.

Discovery of 5-Methylthiazole-Thiazolidinone Conjugates as Potential Anti-Inflammatory Agents: Molecular Target Identification and In Silico Studies.

A series of previously synthesized 5-benzyliden-2-(5-methylthiazole-2-ylimino)thiazoli- din-4-one were evaluated for their anti-inflammatory activity on the basis of PASS predictive outcomes. The predictive compounds were found to demonstrate moderate to good anti-inflammatory activity, and some of them displayed better activity than indomethacin used as the reference drug. Structure-activity relationships revealed that the activity of compounds depends not only on the nature of the substituent but also on its position in the benzene ring. The most active compounds were selected to investigate their possible mechanism of action. COX and LOX activity were determined and found that the title compounds were active only to COX-1 enzymes with an inhibitory effect superior to the reference drug naproxen. As for LOX inhibitory activity, the derivatives failed to show remarkable LOX inhibition. Therefore, COX-1 has been identified as the main molecular target for the anti-inflammatory activity of our compounds. The docking study against COX-1 active site revealed that the residue Arg 120 was found to be responsible for activity. In summary, the 5-thiazol-based thiazolidinone derivatives have been identified as a novel class of selective COX-1 inhibitors.

Triazolo Based-Thiadiazole Derivatives. Synthesis, Biological Evaluation and Molecular Docking Studies.

The goal of this research is to investigate the antimicrobial activity of nineteen previously synthesized 3,6-disubstituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole derivatives. The compounds were tested against a panel of three Gram-positive and three Gram-negative bacteria, three resistant strains, and six fungi. Minimal inhibitory, bactericidal, and fungicidal concentrations were determined by a microdilution method. All of the compounds showed antibacterial activity that was more potent than both reference drugs, ampicillin and streptomycin, against all bacteria tested. Similarly, they were also more active against resistant bacterial strains. The antifungal activity of the compounds was up to 80-fold higher than ketoconazole and from 3 to 40 times higher than bifonazole, both of which were used as reference drugs. The most active compounds (2, 3, 6, 7, and 19) were tested for their inhibition of P. aeruginosa biofilm formation. Among them, compound 3 showed significantly higher antibiofilm activity and appeared to be equipotent with ampicillin. The prediction of the probable mechanism by docking on antibacterial targets revealed that E. coli MurB is the most suitable enzyme, while docking studies on antifungal targets indicated a probable involvement of CYP51 in the mechanism of antifungal activity. Finally, the toxicity testing in human cells confirmed their low toxicity both in cancerous cell line MCF7 and non-cancerous cell line HK-2.

Thiazole Ring-A Biologically Active Scaffold.

BACKGROUND: Thiazole is a good pharmacophore nucleus due to its various pharmaceutical applications. Its derivatives have a wide range of biological activities such as antioxidant, analgesic, and antimicrobial including antibacterial, antifungal, antimalarial, anticancer, antiallergic, antihypertensive, anti-inflammatory, and antipsychotic. Indeed, the thiazole scaffold is contained in more than 18 FDA-approved drugs as well as in numerous experimental drugs. OBJECTIVE: To summarize recent literature on the biological activities of thiazole ring-containing compounds Methods: A literature survey regarding the topics from the year 2015 up to now was carried out. Older publications were not included, since they were previously analyzed in available peer reviews. RESULTS: Nearly 124 research articles were found, critically analyzed, and arranged regarding the synthesis and biological activities of thiazoles derivatives in the last 5 years.

Aldose reductase and protein tyrosine phosphatase 1B inhibitors as a promising therapeutic approach for diabetes mellitus.

Diabetes mellitus is a metabolic disease characterized by high blood glucose levels and usually associated with several chronic pathologies. Aldose reductase and protein tyrosine phosphatase 1B enzymes have identified as two novel molecular targets associated with the onset and progression of type II diabetes and related comorbidities. Although many inhibitors against these enzymes have already found in the field of diabetic mellitus, the research for discovering more effective and selective agents with optimal pharmacokinetic properties continues. In addition, dual inhibition of these target proteins has proved as a promising therapeutic approach. A variety of diverse scaffolds are presented in this review for the future design of potent and selective inhibitors of aldose reductase and protein tyrosine phosphatase 1B based on the most important structural features of both enzymes. The discovery of novel dual aldose reductase and protein tyrosine phosphatase 1B inhibitors could be effective therapeutic molecules for the treatment of insulin-resistant type II diabetes mellitus. The methods used comprise a literature survey and X-ray crystal structures derived from Protein Databank (PDB). Despite the available therapeutic options for type II diabetes mellitus, the inhibitors of aldose reductase and protein tyrosine phosphatase 1B could be two promising approaches for the effective treatment of hyperglycemia and diabetes-associated pathologies. Due to the poor pharmacokinetic profile and low in vivo efficacy of existing inhibitors of both targets, the research turned to more selective and cell-permeable agents as well as multi-target molecules.

Heterocycle Compounds with Antimicrobial Activity.

BACKGROUND: Bacterial infections are a growing problem worldwide causing morbidity and mortality mainly in developing countries. Moreover, the increased number of microorganisms, developing multiple resistances to known drugs, due to abuse of antibiotics, is another serious problem. This problem becomes more serious for immunocompromised patients and those who are often disposed to opportunistic fungal infections. OBJECTIVE: The objective of this manuscript is to give an overview of new findings in the field of antimicrobial agents among five-membered heterocyclic compounds. These heterocyclic compounds especially five-membered attracted the interest of the scientific community not only for their occurrence in nature but also due to their wide range of biological activities. METHODS: To reach our goal, a literature survey that covers the last decade was performed. RESULTS: As a result, recent data on the biological activity of thiazole, thiazolidinone, benzothiazole and thiadiazole derivatives are mentioned. CONCLUSION: It should be mentioned that despite the progress in the development of new antimicrobial agents, there is still room for new findings. Thus, research still continues.

Derivatives of a new heterocyclic system - pyrano[3,4-c][1,2,4]triazolo[4,3-a]pyridines: synthesis, docking analysis and neurotropic activity.

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 GABAA receptor, SERT and 5-HT1A receptor.

5-Adamantan thiadiazole-based thiazolidinones as antimicrobial agents. Design, synthesis, molecular docking and evaluation.

In continuation of our efforts to develop new compounds with antimicrobial properties we describe design, synthesis, molecular docking study and evaluation of antimicrobial activity of seventeen novel 2-{[5-(adamantan-1-yl)-1,3,4-thiadiazol-2-yl]-imino}-5-arylidene-1,3-thiazolidin-4-ones. All compounds showed antibacterial activity against eight Gram positive and Gram negative bacterial species. Twelve out of seventeen compounds were more potent than streptomycin and all compounds exhibited higher potency than ampicillin. Compounds were also tested against three resistant bacterial strains: MRSA, P. aeruginosa and E. coli. The best antibacterial potential against ATCC and resistant strains was observed for compound 8 (2-{[5-(adamantan-1-yl)-1,3,4-thiadiazol-2-yl]-imino}-5-(4-nitrobenzylidene)-1,3thiazolidin-4-one). The most sensitive bacterium appeared to be S. typhimirium, followed by B. cereus while L. monocitogenes and M. flavus were the most resistant. Compounds were also tested for their antifungal activity against eight fungal species. All compounds exhibited antifungal activity better than the reference drugs bifonazole and ketokonazole (3-115 times). It was found that compound 8 appeared again to be the most potent. Molecular docking studies on E. coli MurB, MurA as well as C. albicans CYP 51 and dihydrofolate reductase were used for the prediction of mechanism of antibacterial and antifungal activities confirming the experimental results.

Thiazoles and Thiazolidinones as COX/LOX Inhibitors.

Inflammation is a natural process that is connected to various conditions and disorders such as arthritis, psoriasis, cancer, infections, asthma, etc. Based on the fact that cyclooxygenase isoenzymes (COX-1, COX-2) are responsible for the production of prostaglandins that play an important role in inflammation, traditional treatment approaches include administration of non-steroidal anti-inflammatory drugs (NSAIDs), which act as selective or non-selective COX inhibitors. Almost all of them present a number of unwanted, often serious, side effects as a consequence of interference with the arachidonic acid cascade. In search for new drugs to avoid side effects, while maintaining high potency over inflammation, scientists turned their interest to the synthesis of dual COX/LOX inhibitors, which could provide numerous therapeutic advantages in terms of anti-inflammatory activity, improved gastric protection and safer cardiovascular profile compared to conventional NSAIDs. Τhiazole and thiazolidinone moieties can be found in numerous biologically active compounds of natural origin, as well as synthetic molecules that possess a wide range of pharmacological activities. This review focuses on the biological activity of several thiazole and thiazolidinone derivatives as COX-1/COX-2 and LOX inhibitors.

NOV/CCN3: A New Adipocytokine Involved in Obesity-Associated Insulin Resistance.

Identification of new adipokines that potentially link obesity to insulin resistance represents a major challenge. We recently showed that NOV/CCN3, a multifunctional matricellular protein, is synthesized and secreted by adipose tissue, with plasma levels highly correlated with BMI. NOV involvement in tissue repair, fibrotic and inflammatory diseases, and cancer has been previously reported. However, its role in energy homeostasis remains unknown. We investigated the metabolic phenotype of NOV(-/-) mice fed a standard or high-fat diet (HFD). Strikingly, the weight of NOV(-/-) mice was markedly lower than that of wild-type mice but only on an HFD. This was related to a significant decrease in fat mass associated with an increased proportion of smaller adipocytes and to a higher expression of genes involved in energy expenditure. NOV(-/-) mice fed an HFD displayed improved glucose tolerance and insulin sensitivity. Interestingly, the absence of NOV was associated with a change in macrophages profile (M1-like to M2-like), in a marked decrease in adipose tissue expression of several proinflammatory cytokines and chemokines, and in enhanced insulin signaling. Conversely, NOV treatment of adipocytes increased chemokine expression. Altogether, these results show that NOV is a new adipocytokine that could be involved in obesity-associated insulin-resistance.

Synthesis and biological evaluation of potent antifungal agents.

The last two decades are characterized by major increases in the incidence of systemic fungal infections caused by the yeast Candida albicans, particularly in immunocompromised patients. On the other hand it was observed the increased number of pathogenic microorganisms with multiple resistance to drugs. Also there is a big variety of drugs for the treatment of candidiasis, only two drugs are used for the treatment of infections from Aspergillus fumigatus. Taking into account that the long term therapy with azoles results in resistance a critical need exists for new antifungal agents with fewer side effecgts to treat these life-threatening fungal infections. This review will cover the advances in research of biological activity of different compounds from different chemical classes with focus on their antifungal properties.