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.

Therapeutic Bacteriophages for Gram-Negative Bacterial Infections in Animals and Humans.

Drug-resistant Gram-negative bacterial pathogens are an increasingly serious health threat causing worldwide nosocomial infections with high morbidity and mortality. Of these, the most prevalent and severe are Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii, and Salmonella typhimurium. The extended use of antibiotics has led to the emergence of multidrug resistance in these bacteria. Drug-inactivating enzymes produced by these bacteria, as well as other resistance mechanisms, render drugs ineffective and make treatment of such infections more difficult and complicated. This makes the development of novel antimicrobial agents an urgent necessity. Bacteriophages, which are bacteria-killing viruses first discovered in 1915, have been used as therapeutic antimicrobials in the past, but their use was abandoned due to the widespread availability of antibiotics in the 20th century. The emergence, however, of drug-resistant pathogens has re-affirmed the need for bacteriophages as therapeutic strategies. This review describes the use of bacteriophages as novel agents to combat this rapidly emerging public health crisis by comprehensively enumerating and discussing the innovative use of bacteriophages in both animal models and in patients infected by Gram-negative bacteria.

Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor (rhu GM-CSF) as Adjuvant Therapy for Invasive Fungal Diseases.

Background: Sargramostim (yeast-derived, glycosylated recombinant human granulocyte-macrophage colony-stimulating factor [rhu GM-CSF]) augments innate and adaptive immune responses and accelerates hematopoietic recovery of chemotherapy-induced neutropenia. However, considerably less is known about its efficacy as adjunctive immunotherapy against invasive fungal diseases (IFDs). Methods: The clinical courses of 15 patients with pediatric malignancies and IFDs treated adjunctively with sargramostim at a single institution were analyzed in a retrospective cohort review. Further, a systematic review of published reports of rhu GM-CSF for IFDs was also conducted. Results: Among 65 cases, 15 were newly described pediatric patients and 50 were previously published cases of IFDs treated with rhu GM-CSF. Among the newly reported pediatric patients, IFDs were caused by Candida spp., Trichosporon sp., and molds (Aspergillus spp., Rhizopus sp., Lichtheimia sp., and Scedosporium sp). Twelve (80%) were neutropenic at baseline, and 12 (80%) were refractory to antifungal therapy. Among 12 evaluable patients, the overall response rate was 92% (8 [67%] complete responses, 3 [25%] partial responses, and 1 [8%] stable). Treatment is ongoing in the remaining 3 patients. Among 50 published cases (15 Candida spp., 13 Mucorales, 11 Aspergillus spp., 11 other organisms), 20 (40%) had baseline neutropenia and 36 (72%) were refractory to standard therapy before rhu GM-CSF administration. Consistent with responses in the newly reported patients, the overall response rate in the literature review was 82% (40 [80%] complete responses, 1 [2%] partial response, and 9 [18%] no response). Conclusions: Sargramostim may be a potential adjunctive immunomodulator for selected patients with hematological malignancies and refractory IFDs.

Developing New Treatments for COVID-19 through Dual-Action Antiviral/Anti-Inflammatory Small Molecules and Physiologically Based Pharmacokinetic Modeling.

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.

Thiazole/Thiadiazole/Benzothiazole Based Thiazolidin-4-One Derivatives as Potential Inhibitors of Main Protease of SARS-CoV-2.

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.

Novel antifungal agents in clinical trials.

Invasive fungal diseases due to resistant yeasts and molds are an important and increasing public health threat, likely due to a growing population of immunosuppressed hosts, increases in antifungal resistance, and improvements in laboratory diagnostics.  The significant morbidity and mortality associated with these pathogens bespeaks the urgent need for novel safe and effective therapeutics.  This review highlights promising investigational antifungal agents in clinical phases of development: fosmanogepix, ibrexafungerp, rezafungin, encochleated amphotericin B, oteseconazole (VT-1161), VT-1598, PC945, and olorofim.  We examine three first-in-class members of three novel antifungal classes, as well as new agents within existing antifungal classes with improved safety and tolerability profiles due to enhanced pharmacokinetic and pharmacodynamic properties.

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.