Current Status of Baricitinib as a Repurposed Therapy for COVID-19

The emergence of the COVID-19 pandemic has mandated the instant (re)search for potential drug candidates. In response to the unprecedented situation, it was recognized early that repurposing of available drugs in the market could timely save lives, by skipping the lengthy phases of preclinical and initial safety studies. BenevolentAI’s large knowledge graph repository of structured medical information suggested baricitinib, a Janus-associated kinase inhibitor, as a potential repurposed medicine with a dual mechanism; hindering SARS-CoV2 entry and combatting the cytokine storm; the leading cause of mortality in COVID-19. However, the recently-published Adaptive COVID-19 Treatment Trial-2 (ACTT-2) positioned baricitinib only in combination with remdesivir for treatment of a specific category of COVID-19 patients, whereas the drug is not recommended to be used alone except in clinical trials. The increased pace of data output in all life sciences fields has changed our understanding of data processing and manipulation. For the purpose of drug design, development, or repurposing, the integration of different disciplines of life sciences is highly recommended to achieve the ultimate benefit of using new technologies to mine BIG data, however, the final say remains to be concluded after the drug is used in clinical practice. This review demonstrates different bioinformatics, chemical, pharmacological, and clinical aspects of baricitinib to highlight the repurposing journey of the drug and evaluates its placement in the current guidelines for COVID-19 treatment

Design, synthesis and mechanistic anticancer activity of new acetylated 5-aminosalicylate-thiazolinone hybrid derivatives

The development of hybrid compounds has been widely considered as a promising strategy to circumvent the difficulties that emerge in cancer treatment. The well-established strategy of adding acetyl groups to certain drugs has been demonstrated to enhance their therapeutic efficacy. Based on our previous work, an approach of accommodating two chemical entities into a single structure was implemented to synthesize new acetylated hybrids (HH32 and HH33) from 5-aminosalicylic acid and 4-thiazolinone derivatives. These acetylated hybrids showed potential anticancer activities and distinct metabolomic profile with antiproliferative properties. The in-silico molecular docking predicts a strong binding of HH32 and HH33 to cell cycle regulators, and transcriptomic analysis revealed DNA repair and cell cycle as the main targets of HH33 compounds. These findings were validated using in vitro models. In conclusion, the pleiotropic biological effects of HH32 and HH33 compounds on cancer cells demonstrated a new avenue to develop more potent cancer therapies

Hepatoprotective and antioxidant potential of Nyctanthes arbor-tristis L. leaves against antitubercular drugs induced hepatotoxicity

Context: Nyctanthes arbor-tristis L. (Oleaceae) leaf are used in treatment of malaria, rheumatoid arthritis, chronic fever and enlargement of spleen; however, there is paucity of information on its hepatoprotective and antioxidant potential. Aims: To evaluate hepatoprotective and antioxidant potentials of ethanolic leaf extract of Nyctanthes arbor-tristis L. Methods: After collection and authentication of the vegetal material, ethanolic extract was collected. The combination of antitubercular drugs (isoniazid, rifampicin and pyrazinamide) was used to induce hepatotoxicity in Wistar rats. Hepatoprotective effect was evaluated at doses 125, 250 and 500 mg/kg, body weight by estimating the activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and levels of total bilirubin (TBL). The effects on lipid peroxidation (LPO), reduced glutathione (GSH) and catalase (CAT), superoxide dismutase (SOD) were estimated. Docking study was conducted to anticipate the probable biological targets associated with its hepatoprotective effect. Results: The plant extract dose of 500 mg/kg, body weight significantly declined the levels of AST, ALT, ALP and TBL at (p < 0.001), which is approximately corresponding to the dose of reference compound silymarin and reversed the levels of LPO, GSH, SOD, CAT as compared to silymarin dose. Histopathological studies revealed regeneration of hepatocytes. The docking results suggested that some active constituents of plant leaves potentially interact with human pregnane X receptor, human constitutive androstane receptor and the farnesoid X receptor. Conclusions: The extract of Nyctanthes arbor-tristis L. remarkably possesses hepatoprotective and antioxidant effect and evinced its traditional claim. Future studies should be done to isolate active phytoconstituents for use in drug discovery

In vitro and in vivo efficacy study of cefepime, doripenem, tigecycline, and tetracycline against extended-spectrum beta-lactamases Escherichia coli in chickens

Background and Aim: At present, there are no data about the efficacy of some recent antibiotics on Escherichia coli in broiler chickens in the study area. This study was designed to evaluate the in vitro and in vivo efficacy of cefepime, doripenem, tigecycline, and tetracycline against multidrug-resistant-extended-spectrum beta-lactamases (MDR-ESBLs) producing E. coli in broiler chicks. Materials and Methods: A total of 34 MDR-ESBLs E. coli isolates were used in this study. In vitro evaluation of the antibacterial efficacy of cefepime, doripenem, tigecycline, and tetracycline were performed using disk diffusion and minimum inhibitory concentration (MIC) assays. In vivo evaluation of the efficacy of the antibiotics was perfumed using 180, 2-week-old chicks challenged with MDR-ESBL-producing E. coli strain O78. Chicks were divided into six groups (30 chicks each) according to the treatment regimen. Treatment was administered to chicks in Groups 3-6 intravenously, twice per day for 1 week using one antibiotic per group at concentration 10 times the determined MIC. Chicks in the positive control (Group 1) were challenged and received 0.2 ml of sterile Tryptone Soy Broth (TSB), while those in the negative control (Group 2) were not challenged and received 0.2 ml of sterile TSB. The severity of clinical signs, gross lesions, and mortality rate was scored and compared between groups. Results: All E. coli isolates were sensitive to doripenem and tigecycline, while 88% were sensitive to cefepime and only 23% were sensitive to tetracycline. In vivo antibiotic efficacy evaluation in challenged chicks revealed a significant reduction in the severity of clinical signs, gross lesions, and mortality (3%) in chicks treated with cefepime compared to non-treated chicks (55%). There was no significant effect on the severity of clinical signs, gross lesions, and mortality in chicks treated with doripenem, tigecycline, and tetracycline compared to non-treated chicks. The mortality rates of chicks treated with doripenem, tigecycline, and tetracycline were 57%, 50%, and 90%, respectively. Conclusion: The results of this study indicate that most MDR-ESBLs producing E. coli isolates were sensitive to doripenem, tigecycline, and cefepime. However, in vivo study indicated that only cefepime was effective and resulted in a significant reduction in clinical signs, gross lesions, and mortality in infected chicks. Therefore, cefepime could be used to treat naturally infected chickens with MDR-ESBLs producing strains of E. coli

Molecular study on methicillin-resistant Staphylococcus aureus strains isolated from dogs and associated personnel in Jordan

Objective: To determine the prevalence, genetic relatedness, and pattern of antimicrobial susceptibility in methicillin-resistant Staphylococcus aureus (S. aureus) (MRSA) isolated from household dogs, farm dogs, and stray dogs, compared to isolates from their associated personnel. Methods: MRSA was isolated from 250 nasal swabs (150 swabs from dogs and 100 swabs from humans). PCR assays were used to detect the presence of both the nuc and mecA genes, which confirmed the identity of S. aureus isolates and the presence of methicillin resistance, respectively. Disk diffusion was used to determine the antibiotic susceptibility against 15 antimicrobial agents along with an E-test that determined the minimum inhibitory concentration for oxacillin. Pulsed field gel electrophoresis was conducted to determine the genetic relatedness of MRSA isolates from dogs to those from associated and unassociated personnel. Results: The prevalence of S. aureus in dogs and humans was 12.7% and 10.0% respectively, while the prevalence of MRSA isolates in dogs and humans was 5.3% and 5.0%, respectively. The prevalence of MRSA isolates in household dogs, farm dogs, and stray dogs was 7.8%, 4.7%, and 0.0%, respectively. MRSA isolates demonstrated a significantly higher rate of multi-resistance against three or more antimicrobial agents than methicillin-susceptible S. aureus (MSSA). Trimethoprim-sulphamethoxazole and chloramphenicol were the most effective antibiotics against all MRSA isolates. Pulsed field gel electrophoresis revealed a strong association between dog MRSA isolates and MRSA isolates from strongly associated personnel. Conclusions: MRSA is prevalent in house dogs, as well as in dog rearing centers and among their strongly associated personnel. A strong association was found between the MRSA isolates from dogs and those from humans who are in close contact. In addition, MRSA isolates showed a high rate of multi-resistance compared to MSSA isolates

Imidazothiazole-based potent inhibitors of V600E-B-RAF kinase with promising anti-melanoma activity: biological and computational studies

A series of imidazothiazole derivatives possessing potential activity against melanoma cells were investigated for molecular mechanism of action. The target compounds were tested against V600E-B-RAF and RAF1 kinases. Compound 1zb is the most potent against both kinases with IC50 values 0.978 and 8.2 nM, respectively. It showed relative selectivity against V600E mutant B-RAF kinase. Compound 1zb was also tested against four melanoma cell lines and exerted superior potency (IC50 0.18-0.59 µM) compared to the reference standard drug, sorafenib (IC50 1.95-5.45 µM). Compound 1zb demonstrated also prominent selectivity towards melanoma cells than normal skin cells. It was further tested in whole-cell kinase assay and showed in-cell V600E-B-RAF kinase inhibition with IC50 of 0.19 µM. Compound 1zb induces apoptosis not necrosis in the most sensitive melanoma cell line, UACC-62. Furthermore, molecular dynamic and 3D-QSAR studies were done to investigate the binding mode and understand the pharmacophoric features of this series of compounds

A Review of HER4 (ErbB4) Kinase, Its Impact on Cancer, and Its Inhibitors

HER4 is a receptor tyrosine kinase that is required for the evolution of normal body systems such as cardiovascular, nervous, and endocrine systems, especially the mammary glands. It is activated through ligand binding and activates MAPKs and PI3K/AKT pathways. HER4 is commonly expressed in many human tissues, both adult and fetal. It is important to understand the role of HER4 in the treatment of many disorders. Many studies were also conducted on the role of HER4 in tumors and its tumor suppressor function. Mostly, overexpression of HER4 kinase results in cancer development. In the present article, we reviewed the structure, location, ligands, physiological functions of HER4, and its relationship to different cancer types. HER4 inhibitors reported mainly from 2016 to the present were reviewed as well

Design, synthesis and mechanistic anticancer activity of new acetylated 5-aminosalicylate-thiazolinone hybrid derivatives

Summary: The development of hybrid compounds has been widely considered as a promising strategy to circumvent the difficulties that emerge in cancer treatment. The well-established strategy of adding acetyl groups to certain drugs has been demonstrated to enhance their therapeutic efficacy. Based on our previous work, an approach of accommodating two chemical entities into a single structure was implemented to synthesize new acetylated hybrids (HH32 and HH33) from 5-aminosalicylic acid and 4-thiazolinone derivatives. These acetylated hybrids showed potential anticancer activities and distinct metabolomic profile with antiproliferative properties. The in-silico molecular docking predicts a strong binding of HH32 and HH33 to cell cycle regulators, and transcriptomic analysis revealed DNA repair and cell cycle as the main targets of HH33 compounds. These findings were validated using in vitro models. In conclusion, the pleiotropic biological effects of HH32 and HH33 compounds on cancer cells demonstrated a new avenue to develop more potent cancer therapies

Molecular docking and glucosidase inhibition studies of novel N-arylthiazole-2-amines and Ethyl 2-[aryl(thiazol-2-yl)amino]acetates

This study describes an efficient synthesis of a series of novel ethyl 2-[aryl(thiazol-2-yl)amino]acetates (4a-l) from N-arylthiazole-2-amines (3a-l). The reaction conditions were optimized and the best results were obtained when ethyl chloroacetate was used as alkylating agent and NaH as base in THF. alpha-glucosidase and beta-glucosidase inhibition activities of N-arylthiazole-2-amines (3a-l) and ethyl 2-[aryl(thiazol-2-yl)amino]acetates (4a-l) were determined, which revealed that most of the compounds showed high percentage inhibition towards the enzymes. Among the synthesized compounds, 4e appeared to have the highest inhibition towards alpha-glucosidase having IC50 value of 150.4 +/- 1.9 mu M which was almost two folds as compared to acarbose (336.9 +/- 9.0 mu M) taken as standard. Molecular docking of the compounds 3g, 3f, 4a, and 4e was also performed which showed their bonding modes to the enzyme's active sites via amino and acetate groups, respectively.- A.F. Khan is thankful to Higher Education Commission, Pakistan for providing funding under NRPU project No. 1690 for this research.info:eu-repo/semantics/publishedVersio