Synthesis, Characterization, and Antimicrobial Activity Screening of Some Novel 3-(2-(3-(Substituted benzyloxy)oxetan-3-yl)-3-fluorophenoxy)-8-fluoro-2-methylquinoline Derivatives as Potential Antimycobacterial Agents.

Microbial infections remain a grave threat to global health security due to increasing antibiotic resistance. The coronavirus pandemic has increased the risk of microbial infection. To combat these infections, the search for new therapeutic agents is in high demand. A series of new 3-(2-(3-(substituted benzyloxy)oxetan-3-yl)-3-fluorophenoxy)-8-fluoro-2-methylquinoline (9a-i) derivatives have been synthesized. The structure of synthesized compounds was analyzed by spectroscopic methods. The newly synthesized oxetanyl-quinoline derivatives were evaluated for in vitro antibacterial activity against Escherichia coli (NCIM 2574), Proteus mirabilis (NCIM 2388), Bacillus subtilis (NCIM 2063), Staphylococcus albus (NCIM 2178), and in vitro antifungal activity against Aspergillus niger (ATCC 504) and Candida albicans (NCIM 3100). Six oxetanyl-quinoline derivatives 9a, 9b, 9c, 9d, 9e, and 9h have shown good antibacterial activity against P. mirabilis with MIC 31.25-62.5 µM, 3-(((3-(2-fluoro-6-((8-fluoro-2-methylquinolin-3-yl)oxy)phenyl)oxetan-3-yl)oxy)methyl)benzonitrile (9f) reporting comparable activity against P. mirabilis with respect to the standard drug streptomycin. Compound 9a also showed good activity against B. subtilis with MIC 31.25 µM. The eight compounds 9a, 9b, 9d, 9e, 9f, 9g, 9h, and 9i have shown good antifungal activity against A. niger. The synthesized compounds were also screened for antimycobacterial activity against Mycobacterium tuberculosis H37Rv by MTT assay. Among the nine derivatives, compounds 9b, 9c, 9d, 9f, 9g, 9h, and 9i showed excellent antimycobacterial activity with MIC 3.41-12.23 µM, and two derivatives showed good activity with MIC 27.29-57.73 µM. All the derivatives were further evaluated for cytotoxicity against the Vero cell line and were found to be nontoxic. The in silico study of compounds 9a-i was performed against ATP synthase (PDB ID: 4V1F) and most of the compounds showed the stable and significant binding to ATP synthase, confirming their plausible mode of action as ATP synthase inhibitors. Thus, the significant antimycobacterial activity of 3-(2-(3-(substituted benzyloxy)oxetan-3-yl)-3-fluorophenoxy)-8-fluoro-2-methylquinoline derivatives has suggested that the oxatenyl-quinoline compounds could assist in the development of lead compounds to treat mycobacterial infections.

In silico molecular docking analysis for repurposing therapeutics against multiple proteins from SARS-CoV-2.

SARS-CoV-2 has devastated the world with its rapid spread and fatality. The researchers across the globe are struggling hard to search a drug to treat this infection. Understanding the time constraint, the best approach is to study clinically approved drugs for control of this deadly pandemic of COVID 19. The repurposing of such drugs can be supported with the study of molecular interactions to enhance the possibility of application. The present work is a molecular docking study of proteins responsible for viral propagation namely 3Clpro, Nsp10/16, Spike protein, SARS protein receptor binding domain, Nsp 9 viral single strand binding protein and viral helicase. The protein through virus enters the host cell-human angiotensin-converting enzyme 2 (ACE2) receptor, is also used as a target for molecular docking. The docking was done with most discussed drugs for SARS-CoV-2 like Ritonavir, Lopinavir, Remdesivir, Chloroquine, Hydroxychloroquine (HCQ), routine antiviral drugs like Oseltamivir and Ribavirin. In addition, small molecules with anti-inflammatory actions like Mycophenolic acid (MPA), Pemirolast, Isoniazid and Eriodictyol were also tested. The generated data confirms the potential of Ritonavir, Lopinavir and Remdesivir as a therapeutic candidate against SARS-CoV-2. It is observed that Eriodictyol binds to almost all selected target proteins with good binding energy, suggesting its importance in treatment of COVID 19. Molecular interactions of Ritonavir, Lopinavir and Remdesivir against SARS-CoV-2 proteins enhanced their potential as a candidate drug for treatment of COVID-19. Eriodictyol had emerged as a new repurposing drug that can be used in COVID-19.

Synthesis of new thiazolyl-pyrazolyl-1,2,3-triazole derivatives as potential antimicrobial agents.

A series of 1-substituted benzyl-4-[1-phenyl-3-(4-methyl-2-aryl-1,3-thiazol-5-yl)-1H-pyrazol-4-yl]-1H-1,2,3-triazole derivatives (7a-y) have been synthesized by click reaction of 5-(4-ethynyl-1-phenyl-1H-pyrazol-3-yl)-4-methyl-2-aryl-1,3-thiazole (5a-e) with substituted benzyl azide. The starting compounds 5-(4-ethynyl-1-phenyl-1H-pyrazol-3-yl)-4-methyl-2-aryl-1,3-thiazole (5a-e) were synthesized from corresponding 3-(4-methyl-2-aryl-1,3-thiazol-5-yl)-1-phenyl-1H-pyrazole-4-carbaldehyde (3a-e) by using Ohira-Bestmann reagent. All newly synthesized thiazolyl-pyrazolyl-1,2,3-triazole derivatives were screened for antibacterial activity against two Gram negative strains, Escherichia coli (NCIM 2574), Proteus mirabilis (NCIM 2388), a Gram positive strain Staphylococcus albus (NCIM 2178) and in vitro antifungal activity against Candida albicans (NCIM 3100), Aspergillus niger (ATCC 504) and Rhodotorula glutinis (NCIM 3168). Ten thiazolyl-pyrazolyl-1,2,3-triazole derivatives, 7b, 7g, 7i, 7j, 7k, 7l, 7m, 7n, 7p and 7v exhibited promising antifungal activity against A. niger with MIC 31.5 µg/mL. Compounds 7g, 7i, 7k, 7l and 7m were further evaluated for ergosterol inhibition assay against A. niger cells sample at 31.5 µg/mL concentration. The analysis of sterol inhibition assay revealed that ergosterol biosynthesis is decreased in the fungal samples treated with azole derivatives. Promising antifungal activity suggested that, these compounds could be further promoted for optimization and development which could have the potential to treat against fungal infection.

Comparative Evaluation of Oxidative Stress Modulating and DNA Protective Activities of Aqueous and Methanolic Extracts of Acacia catechu.

Background: Plant-derived bioactive compounds are becoming immensely important as potential drugs. Different solvents are being used for extraction of these phytochemicals. Evaluation of biological activities of aqueous plant extracts is important as water soluble compounds would be more beneficial with respect to certification, safety and commercial issues. Oxidative stress is involved in development of many diseases; therefore, antioxidants are now being looked upon as convincing therapeutics against such diseases. Natural antioxidants are in high demand because of their lesser side effects. This study aims to compare the antioxidant activity of aqueous and methanolic extracts of Acacia catechu-a traditional medicinal plant. Methods: The activity was examined using different in vitro systems including radical scavenging activity, lipid peroxidation and inhibition of •OH radical induced DNA damage using standard protocols. Results: Both aqueous and methanolic extracts of Acacia catechu show significant activities with no differences in the efficacies of water and methanol soluble bioactive compounds. Conclusions: Present study revealed that aqueous extract of A. catechu has equal potential to be used as antioxidants as compared to methanolic extract. This can contribute to increased demand of physiologically compatible bioactive compounds of natural origin.

Tissue specific oxidative stress profile in relation to glycaemic regulation in mice.

BACKGROUND: Diabetes mellitus is a metabolic disorder characterized by hyperglycaemia resulting from uncontrolled glucose regulation. Reactive oxygen species are recognized as one link between hyperglycaemia and diabetic complications. Studies have shown that diabetes mellitus is associated with decreases in antioxidant potential and increased formation of free radicals leading to oxidative stress. The present study was undertaken because an unequivocal demonstration that control of hyperglycaemia can reduce oxidative stress is still lacking. METHODS: In the present study, we investigated oxidative stress profile of normal, streptozotocin-induced diabetic, insulin-treated and untreated diabetic animals. On the one hand, oxidative damage caused to lipids, proteins and DNA was measured. On other hand, antioxidant defense was measured in terms of specific activities of antioxidant enzymes (AOEs) and antioxidant molecules. RESULTS: It was observed that the damage to lipids, proteins and DNA caused by free radicals increased in diabetic animals compared with that in controls. In diabetic animals not treated with insulin, damage to all biological molecules increased further significantly (p ≤ 0.005). Changes in AOEs from different tissues were complex depicting a varied AOE level in different tissues. Insulin treatment significantly improved the oxidative stress profile in all tissues studies. CONCLUSIONS: The control of hyperglycaemia improves oxidative stress profile, that is, the ability of cells to cope up with oxidative stress.

Control of hyperglycemia significantly improves oxidative stress profile of pancreatic islets.

Pancreatic islets are known to express low levels of antioxidant enzymes compared to other tissues and are therefore vulnerable to oxidative stress. Enhancing antioxidant defense mechanisms in pancreatic islets help them to cope better with oxidative stress. Persistent hyperglycemia under diabetic condition leads to continuous generation of reactive oxygen species, and different tissues exposed to this are oxidatively damaged depending on their antioxidant defense. Since islet cells are very poor in their antioxidant defense, our interest was to assess their antioxidant profile under normal, diabetic, insulin treated diabetic and untreated diabetic condition. On one hand, antioxidant defense was measured in terms of antioxidant enzymes and antioxidant molecules while on the other, damage caused to biomolecules was estimated. Our data demonstrate that oxidative damage to all biomolecules increased in islets cultured from diabetic animals, which enhanced further in islets from untreated diabetic animals. Insulin treatment significantly improved oxidative stress profile of islets indicating that the control of hyperglycemia leads to improvement in oxidative stress profile.

Pancreatic islets are very poor in rectifying oxidative DNA damage.

OBJECTIVE: Free radicals that escape scavenging by antioxidant defense damage lipids, proteins, and DNA. Damage to DNA can be repaired. Therefore, both cells' antioxidant defense and their ability to repair oxidatively damaged DNA decide its fate to survive oxidative stress. Pancreatic islets cells with poor antioxidant defense were checked for their ability to remove oxidative damage form DNA. METHODS: For ex vivo DNA repair, assay-cultured pancreatic islets and liver slices were treated with 1 and 10 mM H2O2, respectively, for 30 minutes. After incubation for different time intervals, 8-hydroxy-2'-deoxyguanosine (8-OHdG) in DNA of these cells was estimated using monoclonal antibody raised against 8-OHdG by competitive enzyme-linked immunosorbent assay. For in vitro DNA repair assay, oxidatively damaged pBR322 was incubated with nuclear extracts of islet and liver cells, and 8-OHdG retained in the plasmid was quantitated. RESULTS: Oxidative damage induced by H2O2 was removed quickly and efficiently from DNA by liver cells compared with islet cells. The repair of oxidatively damaged plasmid DNA in vitro was also performed more efficiently (P < 0.05) by nuclear extracts from liver cells compared with islet cell. CONCLUSIONS: We clearly demonstrate that in addition to their low antioxidant defense, islets are very poor in rectifying the oxidative DNA damage.

Bis(quercetinato)oxovanadium IV Reverses Metabolic Changes in Streptozotocin-Induced Diabetic Mice.

Organic vanadium compounds offer several advantages in the treatment of diabetes, yet they are impractical to use because of known side effects. In order to ameliorate the side effects of vanadium, we conjugated it with quercetin to form bis(quercetinato)oxovanadium IV (BQOV). This study evaluates the effect of BQOV treatment on carbohydrate metabolism and overall oxidative stress in streptozotocin-induced (STZ) diabetic mice. Administration of BQOV orally to diabetic mice for 3 weeks led to a reduction of blood glucose levels and the animals exhibited normal glucose tolerance at the end of the study period. The increase in glucose uptake by skeletal muscle and liver as well as the normalization of mRNA levels of G-6-Pase and glucokinase in the liver after BQOV treatment pointed to improvements in carbohydrate metabolism. The analysis of the antioxidant status of serum, liver and pancreas revealed reduced oxidative stress in BQOV-treated animals compared to untreated diabetic controls. Serum analyses for kidney and liver function showed that BQOV treatment provoked total protection of the kidney and partial protection of the liver from diabetogenic insults. The number of insulin-positive cells and the amount of pancreatic insulin in treated mice (1.2038 +/- 0.34 ng/mg tissue) did not account for pancreatic regeneration but suggested an insulin-mimetic action on the part of BQOV. Moreover, administration of BQOV for 3 weeks did not show any visible side-effects. This data indicate that BQOV is a safe and potent agent for diabetes treatment, because it is able to improve carbohydrate metabolism and to reduce overall oxidative stress.

Differential susceptibility of chick and mouse islets to streptozotocin and its co-relation with islet antioxidant status.

Species differences in susceptibility of islets to STZ in different mammals have been well documented. Likewise, failure of diabetes induction in birds by streptozotocin has been reported. We hypothesized that the susceptibility of islets to STZ treatment may be related to generation of reactive oxygen species (ROS) and their antioxidant defense mechanisms. To test this hypothesis, we measured the total ROS generated and estimated the damage caused to the chick islets due to STZ treatment, in terms of lipid peroxidation, protein carbonyl formation and DNA strand breaks and compared it with that of mouse islets. We also compared the activities of antioxidant enzymes like catalase, superoxide dismutase (SOD), glutathione peroxidase (GPX), glutathione reductase (GR) and amount of antioxidant molecules like reduced glutathione (GSH) and uric acid under control and STZ-treated conditions. These studies coupled with viability, functionality and presence of glucose transporter GLUT2 in chick and mouse islets clearly indicated that STZ treatment neither affects viability nor functionality of chick islets whereas those of mouse islets are affected significantly. Here we demonstrate for the first time a correlation between the generation of ROS on STZ treatment and antioxidant status with insensitivity of chick islets to STZ resulting into failure of diabetes induction in chick.

Indian herbs and herbal drugs used for the treatment of diabetes.

Traditional Medicines derived from medicinal plants are used by about 60% of the world's population. This review focuses on Indian Herbal drugs and plants used in the treatment of diabetes, especially in India. Diabetes is an important human ailment afflicting many from various walks of life in different countries. In India it is proving to be a major health problem, especially in the urban areas. Though there are various approaches to reduce the ill effects of diabetes and its secondary complications, herbal formulations are preferred due to lesser side effects and low cost. A list of medicinal plants with proven antidiabetic and related beneficial effects and of herbal drugs used in treatment of diabetes is compiled. These include, Allium sativum, Eugenia jambolana, Momordica charantia Ocimum sanctum, Phyllanthus amarus, Pterocarpus marsupium, Tinospora cordifolia, Trigonella foenum graecum and Withania somnifera. One of the etiologic factors implicated in the development of diabetes and its complications is the damage induced by free radicals and hence an antidiabetic compound with antioxidant properties would be more beneficial. Therefore information on antioxidant effects of these medicinal plants is also included.