We investigated the involvement of peroxisome proliferator activated receptor-γ (PPAR-γ)/endothelial nitric oxide synthase (eNOS) pathway in estradiol mediated protection against ischemia reperfusion ...(I/R)-induced acute kidney injury (AKI) in rats. To induce AKI, rats underwent 40 min of bilateral renal ischemia followed by 24 h of reperfusion. I/R-induced kidney damage was quantified by measuring serum creatinine, creatinine clearance, urea nitrogen, uric acid, potassium, fractional excretion of sodium, microproteinuria, and renal oxidative stress (thiobarbituric acid reactive substances, superoxide anion generation, and reduced glutathione). Hematoxylin eosin stain demonstrated renal histology, while renal expression of apoptotic markers (Bcl-2, Bax), PPAR-γ and eNOS were quantified by immunohistochemistry. Estradiol (1 mg/kg, i.p.) was administered 30 min before I/R in rats. In separate groups, PPAR-γ antagonist, BADGE (30 mg/kg, i.p.), and NOS inhibitor,
l
-NAME (20 mg/kg, i.p.) were administered prior to estradiol treatment, which was followed by I/R in rats. I/R caused significant renal damage as demonstrated by biochemical (serum/urine), renal oxidative stress and histological changes alongwith increased expression of Bax and decreased levels of Bcl-2, PPAR-γ and eNOS, which were prevented by estradiol. Pre-treatment with BADGE and
l
-NAME abolished estradiol mediated renoprotection. Notably, I/R + estradiol + BADGE group revealed decreased expression of PPAR-γ and eNOS in renal tissues. In I/R + estradiol +
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-NAME group, eNOS expression was reduced while PPAR-γ levels remained unchanged. These results suggest that estradiol modulates PPAR-γ which consequently regulates eNOS expression in rat kidneys. We conclude that estradiol protects against I/R-induced AKI through PPAR-γ stimulated eNOS activation in rats.
Despite a significant work that has been done on thiophene, continuous efforts are still being made by the researchers to identify novel heterocyclic compounds with potential bioactivities. Thiophene ...nucleus has been extensively utilized by the researchers across the globe for the development of diverse bioactive heterocycles for hitting a wide range of biological targets. This review throws light on synthetic approaches that have been used for the synthesis of potential thiophene derivatives followed by the depth analysis of them with respect to their pharmacological significance. This review can help the medicinal chemists and researchers to develop novel leads having thiophene nucleus with high efficacy and reduced side effects.
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•Design and synthesis of new coumarin-benzotriazole based molecular hybrids.•Ellman’s method of evaluation demonstrated selective acetylcholinesterase inhibition.•Most potent compound ...showed inhibition against copper-induced Aβ1-42 aggregation.•Potent compound have DNA protective properties against degenerative actions of OH radicals.•Molecular modelling studies with acetylcholinesterase enzyme and Aβ1-42 monomer.
A novel series of triazole tethered coumarin-benzotriazole hybrids based on donepezil skeleton has been designed and synthesized as multifunctional agents for the treatment of Alzheimer’s disease (AD). Among the synthesized compounds 13b showed most potent acetylcholinesterase (AChE) inhibition (IC50 = 0.059 μΜ) with mixed type inhibition scenario. Structure-activity relationship revealed that three-carbon alkyl chain connecting coumarin and triazole is well tolerable for inhibitory potential. Hybrids obtained from 4-hydroxycoumarin and 1-benzotriazole were most potent AChE inhibitors. The inhibitory potential of all compounds against butyrylcholinesterase was also evaluated but all showed negligible activity suggesting that the hybrid molecules are selective AChE inhibitors. 13b (most potent AChE inhibitor) also showed copper-induced Aβ1-42 aggregation inhibition (34.26% at 50 μΜ) and chelating properties for metal ions (Cu2+, Fe2+, and Zn2+) involved in AD pathogenesis along with DNA protective potential against degenerative actions of OH radicals. Molecular modelling studies confirm the potential of 13b in blocking both PAS and CAS of AChE. In addition, interactions of 13b with Aβ1-42 monomer are also streamlined. Therefore, hybrid 13b can act as an effective hit lead molecule for further development of selective AChE inhibitors as multifunctional anti-Alzheimer’s agents.
Keeping in view the emerging need for potent and safer anti‐breast cancer agents as well as the pharmacological attributes of isatin, quinolone, and morpholine derivatives, novel hydrazine‐linked ...morpholinated isatin–quinoline hybrids were designed, synthesized, and evaluated as anti‐breast cancer agents. The synthesized hybrid compounds were preliminarily screened against two breast cancer cell lines (MCF‐7 and MDA‐MB‐231). Almost all synthetics showed potent inhibitory potential against hormone‐positive MCF‐7 cells while being inactive against hormone‐negative MDA‐MB‐231 cells. Potent compounds were further evaluated against the L929 (noncancerous skin fibroblast) cell line and found to be highly selective for MCF‐7 cells over L929 cells. Cell cycle analysis confirmed that the most potent compound AS‐4 (MCF‐7: GI50 = 4.36 µM) causes mitotic arrest at the G2/M phase. Due to higher selectivity toward estrogen receptor alpha (ERα)‐dependent MCF‐7 cells, various binding interactions of AS‐4 with ERα are also streamlined, suggesting the capability of AS‐4 to completely block ERα. Overall, the study suggests that AS‐4 can act as a potential lead for further development of potent and safer anti‐breast cancer agents.
New hydrazine‐linked morpholinated isatin–quinoline hybrids were designed, synthesized, and evaluated as anti‐breast cancer agents. Almost all synthetics showed potent inhibitory potential against hormone‐positive MCF‐7 cells while being inactive against hormone‐negative MDA‐MB‐231 cells. Cell cycle analysis confirmed that the most potent compound AS‐4 causes mitotic arrest at the G2/M phase. AS‐4 may work by completely blocking estrogen receptor alpha.
In the present study, a series of 2,4-diarylpyrano3,2-cchromen-5(4H)-ones were synthesised and evaluated as antiproliferative agents. The compounds were evaluated against a panel of human cancer cell ...lines. CH-1 exhibited significant cytoxicity against HCT 116 cell lines with an IC50 value of 1.4 and 4.3 µM against “MiaPaCa-2” cell lines. The compound CH-1 was found to induce apoptosis as evidenced by phase contrast microscopy, Hoechst 33258 staining and mitochondrial membrane potential (MMP) loss. The cell phase distribution studies indicated that the apoptotic population increased from 10.22% in the control sample to 57.19% in a sample treated with 20 µM compound CH-1.
Candida infections are most prominent among fungal infections majorly target immunocompromised and hospitalized patients and cause significant morbidity and mortality. Candida albicans is the ...notorious and most prevalent among all pathogenic Candida strains. Its emerging resistance toward available antifungal agents making it hard to tackle and emerging as global healthcare emergency. Simultaneously, 1,2,3‐triazole nucleus is a privileged scaffold that is gaining importance in antifungal drug development due to being a prominent bioactive linker and isostere of triazole based antifungal class core 1,2,4‐triazole. Numerous reports have been updated in scientific literature in last few decades related to utilization of 1,2,3‐triazole nucleus in antifungal drug development against Candida albicans. Present review will shed light on various preclinical studies focused on development of 1,2,3‐triazole derivatives targeting Candida albicans along with brief highlight on clinical trials and newly approved drugs. Structure‐activity relationship has been precisely discussed for each architect along with future perspective that will help medicinal chemists in design and development of potent antifungal agents for tackling infections derived from Candida albicans.
Xanthine oxidase, a molybdo-flavoenzyme, and an isoform of xanthine dehydrogenase both exist as xanthine oxidoreductase and are responsible for purine catabolism. Xanthine oxidase is more involved in ...pathological conditions when extensively modulated. Elevation of xanthine oxidase is not only the prime cause of gout but is also responsible for various hyperuricemia associated pathological conditions like diabetes, chronic wounds, cardiovascular disorders, Alzheimer's disease,
etc.
Currently available xanthine oxidase inhibitors in clinical practice (allopurinol, febuxostat and topiroxostat) suffer from fatal side effects that pose a serious problem to the healthcare system, raising global emergency to develop novel, potent and safer xanthine oxidase inhibitors. This review will provide key and systematic information about: a. design strategies (inspired from both marketed drugs in clinical practice and natural products), structural insights and pharmacological output (xanthine oxidase inhibition and associated activities) of various pre-clinical candidates reported by various research groups across the globe in the past two decades; b. patented xanthine oxidase inhibitors published in the last three decades and c. clinical trials and their outcomes on approved drug candidates. Information generated in this review has suggested fragment-based drug design (FBDD) and molecular hybridization techniques to be most suitable for development of desired xanthine oxidase inhibitors as one provides high selectivity toward the enzyme and the other imparts multifunctional properties to the structure and both may possess capabilities to surpass the limitations of currently available clinical drugs. All in combination will exclusively update researchers working on xanthine oxidase inhibitors and allied areas and potentially help in designing rational, novel, potent and safer xanthine oxidase inhibitors that can effectively tackle xanthine oxidase related disease conditions and disorders.
Xanthine oxidase, a molybdo-flavoenzyme, and an isoform of xanthine dehydrogenase both exist as xanthine oxidoreductase and are responsible for purine catabolism.
Non-small cell lung cancer, head and neck cancer, glioblastoma, and various other cancer types often demonstrate persistent elevation in EGFR tyrosine kinase activity due to acquired mutations in its ...kinase domain. Any alteration in the EGFR is responsible for triggering the upregulation of tumor angiogenic pathways, such as the PI3k-AKT-mTOR pathway, MAPK-ERK pathway and PLC-Ƴ pathway, which are critically involved in promoting tumor angiogenesis in cancer cells. The emergence of frequently occurring EGFR kinase domain mutations (L858R/T790M/C797S) that confer resistance to approved therapeutic agents has presented a significant challenge for researchers aiming to develop effective and well-tolerated treatments against tumor angiogenesis. In this study, we directed our efforts towards the rational design and development of novel quinazoline derivatives with the potential to act as antagonists against both wild-type and mutant EGFR. Our approach encompasing the application of advanced drug design strategies, including structure-based virtual screening, molecular docking, molecular dynamics, metabolic reactivity and cardiotoxicity prediction studies led to the identification of two prominent lead compounds: QU648, for EGFRwt inhibition and QU351, for EGFRmt antagonism. The computed binding energies of selected leads and their molecular dynamics simulations exhibited enhanced conformational stability of QU648 and QU351 when compared to standard drugs Erlotinib and Afatinib. Notably, the lead compounds also demonstrated promising pharmacokinetic properties, metabolic reactivity, and cardiotoxicity profiles. Collectively, the outcomes of our study provide compelling evidence supporting the potential of QU648 and QU351 as prominent anti-angiogenic agents, effectively inhibiting EGFR activity across various cancer types harboring diverse EGFR mutations.Communicated by Ramaswamy H. Sarma.
Keeping in view various pharmacological attributes of indole and coumarin derivatives, a new series of indolindione–coumarin molecular hybrids was rationally designed and synthesized. All synthesized ...hybrid molecules were evaluated for their antimicrobial potential against Gram-negative bacterial strains (Escherichia coli and Salmonella enterica), Gram-positive bacterial strains (Staphylococcus aureus and Mycobacterium smegmatis), and four fungal strains (Candida albicans, Alternaria mali, Penicillium sp., and Fusarium oxysporum) by using the agar gel diffusion method. Among all synthetics, compounds K-1 and K-2 were found to be the best antimicrobial agents with the minimum inhibitory concentration values of 30 and 312 μg/mL, against Penicillium sp. and S. aureus, respectively. The biological data revealed some interesting facts about the structure–activity relationship which state that the electronic environment on the indolinedione moiety and carbon chain length between indolinedione and triazole moieties considerably affect the antimicrobial potential of the synthesized hybrids. Various types of binding interactions of K-2 within the active site of S. aureus dihydrofolate reductase were also streamlined by molecular modeling studies, which revealed the possible mechanism for potent antibacterial activity of the compound.
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