18 results on '"Belal, Ahmed S. F."'
Search Results
2. Insights on the in-vitro binding interaction between donepezil and bovine serum albumin
- Author
-
El Gammal, Reem N., Elmansi, Heba, El-Emam, Ali A., Belal, Fathalla, Elzahhar, Perihan A., Belal, Ahmed S. F., and Hammouda, Mohammed E. A.
- Published
- 2023
- Full Text
- View/download PDF
3. Bioconjugation in Drug Delivery: Practical Perspectives and Future Perceptions
- Author
-
Elzahhar, Perihan, primary, Belal, Ahmed S. F., additional, Elamrawy, Fatema, additional, Helal, Nada A., additional, and Nounou, Mohamed Ismail, additional
- Published
- 2019
- Full Text
- View/download PDF
4. Inclusion of Nitrofurantoin into the Realm of Cancer Chemotherapy via Biology-Oriented Synthesis and Drug Repurposing
- Author
-
Elzahhar, Perihan A., primary, Nematalla, Hisham A., additional, Al-Koussa, Houssam, additional, Abrahamian, Carla, additional, El-Yazbi, Amira F., additional, Bodgi, Larry, additional, Bou-Gharios, Jolie, additional, Azzi, Joyce, additional, Al Choboq, Joelle, additional, Labib, Hala F., additional, Kheir, Wassim Abou, additional, Abu-Serie, Marwa M., additional, Elrewiny, Mohamed A., additional, El-Yazbi, Ahmed F., additional, and Belal, Ahmed S. F., additional
- Published
- 2023
- Full Text
- View/download PDF
5. Challenging inflammatory process at molecular, cellular and in vivo levels via some new pyrazolyl thiazolones
- Author
-
Elzahhar, Perihan A., Alaaeddine, Rana A., Nassra, Rasha, Ismail, Azza, Labib, Hala F., Temraz, Mohamed G., Belal, Ahmed S. F., and El-Yazbi, Ahmed F.
- Abstract
The work reported herein describes the synthesis of a new series of anti-inflammatory pyrazolyl thiazolones. In addition to COX-2/15-LOX inhibition, these hybrids exerted their anti-inflammatory actions through novel mechanisms. The most active compounds possessed COX-2 inhibitory activities comparable to celecoxib (IC50 values of 0.09–0.14 µM) with significant 15-LOX inhibitory activities (IC50s 1.96 to 3.52 µM). Upon investigation of their in vivo anti-inflammatory activities and ulcerogenic profiles, these compounds showed activity patterns equivalent or more superior to diclofenac and/or celecoxib. Intriguingly, the most active compounds were more effective than diclofenac in suppressing monocyte-to-macrophage differentiation and inflammatory cytokine production by activated macrophages, as well as their ability to induce macrophage apoptosis. The latter finding potentially adds a new dimension to the previously reported anti-inflammatory mechanisms of similar compounds. These compounds were effectively docked into COX-2 and 15-LOX active sites. Also, in silico predictions confirmed the appropriateness of these compounds as drug-like candidates.
- Published
- 2021
- Full Text
- View/download PDF
6. Challenging inflammatory process at molecular, cellular and in vivo levels via some new pyrazolyl thiazolones
- Author
-
Elzahhar, Perihan A., primary, Alaaeddine, Rana A., additional, Nassra, Rasha, additional, Ismail, Azza, additional, Labib, Hala F., additional, Temraz, Mohamed G., additional, Belal, Ahmed S. F., additional, and El-Yazbi, Ahmed F., additional
- Published
- 2021
- Full Text
- View/download PDF
7. Development of new fluorescent protein biosensors
- Author
-
Belal, Ahmed S. F.
- Published
- 2013
- Full Text
- View/download PDF
8. Chromone-based small molecules for multistep shutdown of arachidonate pathway: Simultaneous inhibition of COX-2, 15-LOX and mPGES-1 enzymes.
- Author
-
Elzahhar PA, Orioli R, Hassan NW, Gobbi S, Belluti F, Labib HF, El-Yazbi AF, Nassra R, Belal ASF, and Bisi A
- Subjects
- Rats, Animals, Cyclooxygenase 2 metabolism, Cyclooxygenase 1 metabolism, Arachidonic Acids, Edema chemically induced, Edema drug therapy, Molecular Docking Simulation, Cyclooxygenase 2 Inhibitors pharmacology, Cyclooxygenase 2 Inhibitors therapeutic use, Arachidonate 5-Lipoxygenase metabolism, Structure-Activity Relationship, Lipoxygenase Inhibitors chemistry, Anti-Inflammatory Agents pharmacology
- Abstract
As a new approach to the management of inflammatory disorders, a series of chromone-based derivatives containing a (carbamate)hydrazone moiety was designed and synthesized. The compounds were assessed for their ability to inhibit COX-1/2, 15-LOX, and mPGES-1, as a combination that should effectively impede the arachidonate pathway. Results revealed that the benzylcarbazates (2a-c) demonstrated two-digit nanomolar COX-2 inhibitory activities with reasonable selectivity indices. They also showed appreciable 15-LOX inhibition, in comparison to quercetin. Further testing of these compounds for mPGES-1 inhibition displayed promising activities. Intriguingly, compounds 2a-c were capable of suppressing edema in the formalin-induced rat paw edema assay. They exhibited an acceptable gastrointestinal safety profile regarding ulcerogenic liabilities in gross and histopathological examinations. Additionally, upon treatment with the test compounds, the expression of the anti-inflammatory cytokine IL-10 was elevated, whereas that of TNF-α, iNOS, IL-1β, and COX-2 were downregulated in LPS-challenged RAW264.7 macrophages. Docking experiments into the three enzymes showed interesting binding profiles and affinities, further substantiating their biological activities. Their in silico physicochemical and pharmacokinetic parameters were advantageous., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
9. Thermogenic Modulation of Adipose Depots: A Perspective on Possible Therapeutic Intervention with Early Cardiorenal Complications of Metabolic Impairment.
- Author
-
El-Yazbi AF, Elrewiny MA, Habib HM, Eid AH, Elzahhar PA, and Belal ASF
- Subjects
- Humans, Adipose Tissue metabolism, Adipose Tissue pathology, Obesity complications, Obesity metabolism, Thermogenesis, Inflammation complications, Inflammation metabolism, Hypoxia metabolism, Hypoxia pathology, Uncoupling Protein 1 metabolism, Adipose Tissue, Brown metabolism, Adipose Tissue, Brown pathology, Kidney Diseases drug therapy, Kidney Diseases etiology, Kidney Diseases metabolism
- Abstract
Cardiovascular complications of diabetes and obesity remain a major cause for morbidity and mortality worldwide. Despite significant advances in the pharmacotherapy of metabolic disease, the available approaches do not prevent or slow the progression of complications. Moreover, a majority of patients present with significant vascular involvement at early stages of dysfunction prior to overt metabolic changes. The lack of disease-modifying therapies affects millions of patients globally, causing a massive economic burden due to these complications. Significantly, adipose tissue inflammation was implicated in the pathogenesis of metabolic syndrome, diabetes, and obesity. Specifically, perivascular adipose tissue (PVAT) and perirenal adipose tissue (PRAT) depots influence cardiovascular and renal structure and function. Accumulating evidence implicates localized PVAT/PRAT inflammation as the earliest response to metabolic impairment leading to cardiorenal dysfunction. Increased mitochondrial uncoupling protein 1 (UCP1) expression and function lead to PVAT/PRAT hypoxia and inflammation as well as vascular, cardiac, and renal dysfunction. As UCP1 function remains an undruggable target so far, modulation of the augmented UCP1-mediated PVAT/PRAT thermogenesis constitutes a lucrative target for drug development to mitigate early cardiorenal involvement. This can be achieved either by subtle targeted reduction in UCP-1 expression using innovative proteolysis activating chimeric molecules (PROTACs) or by supplementation with cyclocreatine phosphate, which augments the mitochondrial futile creatine cycling and thus decreases UCP1 activity, enhances the efficiency of oxygen use, and reduces hypoxia. Once developed, these molecules will be first-in-class therapeutic tools to directly interfere with and reverse the earliest pathology underlying cardiac, vascular, and renal dysfunction accompanying the early metabolic deterioration. SIGNIFICANCE STATEMENT: Adipose tissue dysfunction plays a major role in the pathogenesis of metabolic diseases and their complications. Although mitochondrial alterations are common in metabolic impairment, it was only recently shown that the early stages of metabolic challenge involve inflammatory changes in select adipose depots associated with increased uncoupling protein 1 thermogenesis and hypoxia. Manipulating this mode of thermogenesis can help mitigate the early inflammation and the consequent cardiorenal complications., (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)
- Published
- 2023
- Full Text
- View/download PDF
10. Modulating leishmanial pteridine metabolism machinery via some new coumarin-1,2,3-triazoles: Design, synthesis and computational studies.
- Author
-
Hassan NW, Sabt A, El-Attar MAZ, Ora M, Bekhit AEA, Amagase K, Bekhit AA, Belal ASF, and Elzahhar PA
- Subjects
- Animals, Humans, Chlorocebus aethiops, Coumarins chemistry, Pteridines pharmacology, Triazoles pharmacology, Triazoles chemistry, Vero Cells, Antiprotozoal Agents, Leishmania
- Abstract
In accordance with WHO statistics, leishmaniasis is one of the top neglected tropical diseases, affecting around 700 000 to one million people per year. To that end, a new series of coumarin-1,2,3-triazole hybrid compounds was designed and synthesized. All new compounds exerted higher activity than miltefosine against L. major promastigotes and amastigotes. Seven compounds showed single digit micromolar IC
50 values whereas three compounds (13c, 14b and 14c) displayed submicromolar potencies. A mechanistic study to elucidate the antifolate-dependent activity of these compounds revealed that folic and folinic acids abrogated their antileishmanial effects. These compounds exhibited high safety margins in normal VERO cells, expressed as high selectivity indices. Docking simulation studies on the folate pathway enzymes pteridine reductase and DHFR-TS imparted strong theoretical support to the observed biological activities. Besides, docking experiments on human DHFR revealed minimal binding interactions thereby highlighting the selectivity of these compounds. Predicted in silico physicochemical and pharmacokinetic parameters were adequate. In view of this, the structural characteristics of these compounds demonstrated their suitability as antileishmanial lead compounds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)- Published
- 2023
- Full Text
- View/download PDF
11. Transforming iodoquinol into broad spectrum anti-tumor leads: Repurposing to modulate redox homeostasis.
- Author
-
Chaaban I, Hafez H, AlZaim I, Tannous C, Ragab H, Hazzaa A, Ketat S, Ghoneim A, Katary M, Abd-Alhaseeb MM, Zouein FA, Albohy A, Amer AN, El-Yazbi AF, and Belal ASF
- Subjects
- Antineoplastic Agents metabolism, Antineoplastic Agents pharmacology, Apoptosis drug effects, Binding Sites, Cell Cycle Checkpoints drug effects, Drug Screening Assays, Antitumor, Humans, MCF-7 Cells, Molecular Docking Simulation, NAD metabolism, NAD(P)H Dehydrogenase (Quinone) antagonists & inhibitors, NAD(P)H Dehydrogenase (Quinone) metabolism, Oxidation-Reduction, Reactive Oxygen Species metabolism, Structure-Activity Relationship, Antineoplastic Agents chemistry, Drug Repositioning, Iodoquinol chemistry
- Abstract
We managed to repurpose the old drug iodoquinol to a series of novel anticancer 7-iodo-quinoline-5,8-diones. Twelve compounds were identified as inhibitors of moderate to high potency on an inhouse MCF-7 cell line, of which 2 compounds (5 and 6) were capable of reducing NAD level in MCF-7 cells in concentrations equivalent to half of their IC
50 s, potentially due to NAD(P)H quinone oxidoreductase (NQO1) inhibition. The same 2 compounds (5 and 6) were capable of reducing p53 expression and increasing reactive oxygen species levels, which further supports the NQO-1 inhibitory activity. Furthermore, 4 compounds (compounds 5-7 and 10) were qualified by the Development Therapeutic Program (DTP) division of the National Cancer Institute (NCI) for full panel five-dose in vitro assay to determine their GI50 on the 60 cell lines. All five compounds showed broad spectrum sub-micromolar to single digit micromolar GI50 against a wide range of cell lines. Cell cycle analysis and dual staining assays with annexin V-FITC/propidium iodide on MCF-7 cells confirmed the capability of the most active compound (compound 5) to induce cell cycle arrest at Pre-G1 and G2/M phases as well as apoptosis. Both cell cycle arrest and apoptosis were affirmed at the molecular level by the ability of compound 5 to enhance the expression levels of caspase-3 and Bax together with suppressing that of CDK1 and Bcl-2. Additionally, an anti-angiogenic effect was evident with compound 5 as supported by the decreased expression of VEGF. Interesting binding modes within NQO-1 active site had been identified and confirmed by both molecular docking and dymanic experiments., (Copyright © 2021 Elsevier Inc. All rights reserved.)- Published
- 2021
- Full Text
- View/download PDF
12. The Emerging Role of COX-2, 15-LOX and PPARγ in Metabolic Diseases and Cancer: An Introduction to Novel Multi-target Directed Ligands (MTDLs).
- Author
-
Alaaeddine RA, Elzahhar PA, AlZaim I, Abou-Kheir W, Belal ASF, and El-Yazbi AF
- Subjects
- Arachidonate 15-Lipoxygenase, Cyclooxygenase 2, Humans, Ligands, PPAR gamma, Metabolic Diseases drug therapy, Neoplasms drug therapy
- Abstract
Emerging evidence supports an intertwining framework for the involvement of different inflammatory pathways in a common pathological background for a number of disorders. Of importance are pathways involving arachidonic acid metabolism by cyclooxygenase-2 (COX-2) and 15-lipoxygenase (15-LOX). Both enzyme activities and their products are implicated in a range of pathophysiological processes encompassing metabolic impairment leading to adipose inflammation and the subsequent vascular and neurological disorders, in addition to various pro- and antitumorigenic effects. A further layer of complexity is encountered by the disparate, and often reciprocal, modulatory effect COX-2 and 15-LOX activities and metabolites exert on each other or on other cellular targets, the most prominent of which is peroxisome proliferator-activated receptor gamma (PPARγ). Thus, effective therapeutic intervention with such multifaceted disorders requires the simultaneous modulation of more than one target. Here, we describe the role of COX-2, 15-LOX, and PPARγ in cancer and complications of metabolic disorders, highlight the value of designing multi-target directed ligands (MTDLs) modifying their activity, and summarizing the available literature regarding the rationale and feasibility of design and synthesis of these ligands together with their known biological effects. We speculate on the potential impact of MTDLs in these disorders as well as emphasize the need for structured future effort to translate these early results facilitating the adoption of these, and similar, molecules in clinical research., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
- Published
- 2021
- Full Text
- View/download PDF
13. Expanding the anticancer potential of 1,2,3-triazoles via simultaneously targeting Cyclooxygenase-2, 15-lipoxygenase and tumor-associated carbonic anhydrases.
- Author
-
Elzahhar PA, Abd El Wahab SM, Elagawany M, Daabees H, Belal ASF, El-Yazbi AF, Eid AH, Alaaeddine R, Hegazy RR, Allam RM, Helmy MW, Bahaa Elgendy, Angeli A, El-Hawash SA, and Supuran CT
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Proliferation drug effects, Cells, Cultured, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Humans, Molecular Structure, Structure-Activity Relationship, Triazoles chemical synthesis, Triazoles chemistry, Antineoplastic Agents pharmacology, Arachidonate 15-Lipoxygenase metabolism, Carbonic Anhydrases metabolism, Cyclooxygenase 2 metabolism, Enzyme Inhibitors pharmacology, Triazoles pharmacology
- Abstract
Cancer is a multifactorial disorder involving multiplicity of interrelated signaling pathways and molecular targets. To that end, a multi-target design strategy was adopted to develop some 1,2,3-triazoles hybridized with some pharmacophoric anticancer fragments, as first-in-class simultaneous inhibitors of COX-2, 15-LOX and tumor associated carbonic anhydrase enzymes. Results revealed that compounds 5a, 5d, 8b and 8c were potent inhibitors of COX-2 and 15-LOX enzymes. COX-2 inhibitory activity was further demonstrated by the inhibition of the accumulation of 6-keto-PGF1α, a metabolite of COX-2 products in two cancer cell lines. The sulfonamide bearing derivatives 5d and 8c were effective nanomolar and submicromolar inhibitors of tumor associated hCA XII isoform, respectively. Strong to moderate inhibitory activities were observed in the in vitro antiproliferative assay on lung (A549), liver (HepG2) and breast (MCF7) cancer cell lines (IC
50 2.37-28.5 μM) with high safety margins on WI-38 cells. A cytotoxic advantage of CA inhibition was observed as an increased activity against tumor cell lines expressing CA IX/XII. Further mechanistic clues for the anticancer activities of compound 5a and its sulfonamide analog 5d were derived from induction of cell cycle arrest at G2/M phase. They also triggered apoptosis via increasing expression levels of caspase-9 and Bax together with suppressing that of Bcl-2. The in vitro anti-tumor activity was reflected as reduced tumor size upon treatment with 8c in an in vivo cancer xenograft model. Docking experiments on the target enzymes supported their in vitro data and served as further molecular evidence. In silico calculations and ligand efficiency indices were promising. In light of these data, such series could offer new structural insights into the understanding and development of multi-target COX-2/15-LOX/hCA inhibitors for anticancer outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)- Published
- 2020
- Full Text
- View/download PDF
14. Shooting three inflammatory targets with a single bullet: Novel multi-targeting anti-inflammatory glitazones.
- Author
-
Elzahhar PA, Alaaeddine R, Ibrahim TM, Nassra R, Ismail A, Chua BSK, Frkic RL, Bruning JB, Wallner N, Knape T, von Knethen A, Labib H, El-Yazbi AF, and Belal ASF
- Subjects
- Animals, Anti-Inflammatory Agents pharmacology, Arachidonate 15-Lipoxygenase drug effects, Cyclooxygenase 2 Inhibitors pharmacology, Humans, Ligands, Molecular Docking Simulation, PPAR gamma agonists, Protein Binding, Thiazolidinediones chemistry, Thiazolidinediones therapeutic use, Anti-Inflammatory Agents chemistry, Drug Design, Thiazolidinediones pharmacology
- Abstract
In search for effective multi-targeting drug ligands (MTDLs) to address low-grade inflammatory changes of metabolic disorders, we rationally designed some novel glitazones-like compounds. This was achieved by incorporating prominent pharmacophoric motifs from previously reported COX-2, 15-LOX and PPARγ ligands. Challenging our design with pre-synthetic docking experiments on PPARγ showed encouraging results. In vitro tests have identified 4 compounds as simultaneous partial PPARγ agonist, potent COX-2 antagonist (nanomolar IC
50 values) and moderate 15-LOX inhibitor (micromolar IC50 values). We envisioned such outcome as a prototypical balanced modulation of the 3 inflammatory targets. In vitro glucose uptake assay defined six compounds as insulin-sensitive and the other two as insulin-independent glucose uptake enhancers. Also, they were able to induce PPARγ nuclear translocation in immunohistochemical analysis. Their anti-inflammatory potential has been translated to effective inhibition of monocyte to macrophage differentiation, suppression of LPS-induced inflammatory cytokine production in macrophages, as well as significant in vivo anti-inflammatory activity. Ligand co-crystallized PPARγ X-ray of one of MTDLs has identified new clues that could serve as structural basis for its partial agonism. Docking of the most active compounds into COX-2 and 15-LOX active sites, pinpointed favorable binding patterns, similar to those of the co-crystallized ligands. Finally, in silico assessment of pharmacokinetics, physicochemical properties, drug-likeness and ligand efficiency indices was performed. Hence, we anticipate that the prominent biological profile of such series will rationalize relevant anti-inflammatory drug development endeavors., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)- Published
- 2019
- Full Text
- View/download PDF
15. Tackling neuroinflammation and cholinergic deficit in Alzheimer's disease: Multi-target inhibitors of cholinesterases, cyclooxygenase-2 and 15-lipoxygenase.
- Author
-
AlFadly ED, Elzahhar PA, Tramarin A, Elkazaz S, Shaltout H, Abu-Serie MM, Janockova J, Soukup O, Ghareeb DA, El-Yazbi AF, Rafeh RW, Bakkar NZ, Kobeissy F, Iriepa I, Moraleda I, Saudi MNS, Bartolini M, and Belal ASF
- Subjects
- Alzheimer Disease pathology, Animals, Cell Line, Cholinesterase Inhibitors chemistry, Cyclooxygenase 2 Inhibitors chemistry, Drug Design, Humans, Lipoxygenase Inhibitors chemistry, Mice, Molecular Docking Simulation, Neurons drug effects, Neurons enzymology, PC12 Cells, Rats, Semicarbazides chemistry, Semicarbazides pharmacology, Triazoles chemistry, Triazoles pharmacology, Acetylcholine deficiency, Alzheimer Disease drug therapy, Inflammation drug therapy, Neurons pathology
- Abstract
Neuroinflammation and cholinergic deficit are key detrimental processes involved in Alzheimer's disease. Hence, in the search for novel and effective treatment strategies, the multi-target-directed ligand paradigm was applied to the rational design of two series of new hybrids endowed with anti-inflammatory and anticholinesterase activity via triple targeting properties, namely able to simultaneously hit cholinesterases, cyclooxygenase-2 (COX-2) and 15-lipoxygenase (15-LOX) enzymes. Among the synthesized compounds, triazoles 5b and 5d, and thiosemicarbazide hybrid 6e emerged as promising new hits, being able to effectively inhibit human butyrylcholinesterase (hBChE), COX-2 and 15-LOX enzymes with a higher inhibitory potency than the reference inhibitors tacrine (for hBChE inhibition), celecoxib (for COX-2 inhibition) and both NDGA and Zileuton (for 15-LOX inhibition). In addition, compound 6e proved to be a submicromolar mixed-type inhibitor of human acetylcholinesterase (hAChE). The anti-neuroinflammatory activity of the three most promising hybrids was confirmed in a cell-based assay using PC12 neuron cells, showing decreased expression levels of inflammatory cytokines IL-1β and TNF-α. Importantly, despite the structural resemblance to tacrine, they showed ideal safety profiles on hepatic and murine brain cell lines and were safe up to 100 μM when assayed in PC12 cells. All three hybrids were also predicted to have superior BBB permeability than tacrine in the PAMPA assay, and good physicochemical properties, drug-likeness and ligand efficiency indices. Finally, molecular docking studies highlighted key structural elements impacting selectivity and activity toward the selected target enzymes. To the best of our knowledge, compounds 5b, 5d and 6e are the first balanced, safe and multi-target compounds hitting the disease at the three mentioned hubs., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
16. Click chemistry inspired copper sulphide nanoparticle-based fluorescence assay of kanamycin using DNA aptamer.
- Author
-
Belal ASF, Ismail A, Elnaggar MM, and Belal TS
- Subjects
- Humans, Kanamycin blood, Kanamycin chemistry, Limit of Detection, Linear Models, Reproducibility of Results, Spectrometry, Fluorescence methods, Aptamers, Nucleotide chemistry, Click Chemistry methods, Copper chemistry, Kanamycin analysis, Metal Nanoparticles chemistry
- Abstract
A highly selective and sensitive fluorescence assay for kanamycin has been developed that depends on complementation of two splits of DNA aptamer. One DNA split was labeled with CuS nanoparticle and the other was decorated with biotin, which enabled coupling with streptavidin magnesphere paramagnetic particles (PMPs). Complementation of the two-aptamer splits happened only in the presence of kanamycin and the subsequent sandwich was separated via a magnet. The released Cu(II) was reduced to Cu(I) by sodium ascorbate and finally catalyzed the click reaction between fluorogenic 3-azido-7-hydroxycoumarin and propargyl alcohol to afford the corresponding fluorescent 1,4-disubstituted-1,2,3-triazole. The fluorescence signal produced (λ
ex. = 365 nm, λem. = 470 nm) was dependent on kanamycin concentration. Fluorescence signal amplification was found to be in good linear relationship with the logarithm of kanamycin concentration in the range of 0.04-20 nM. Furthermore, the proposed assay showed a good reproducibility, high selectivity and low detection limits for kanamycin determination. In addition, the capability of the proposed method to detect kanamycin in biological samples with satisfactory results was demonstrated., (Copyright © 2018 Elsevier B.V. All rights reserved.)- Published
- 2018
- Full Text
- View/download PDF
17. Anti-leishmanial click modifiable thiosemicarbazones: Design, synthesis, biological evaluation and in silico studies.
- Author
-
Temraz MG, Elzahhar PA, El-Din A Bekhit A, Bekhit AA, Labib HF, and Belal ASF
- Subjects
- Animals, Chlorocebus aethiops, Click Chemistry, Drug Design, Humans, Leishmania major enzymology, Leishmaniasis, Cutaneous drug therapy, Leishmaniasis, Cutaneous parasitology, Molecular Docking Simulation, Oxidoreductases metabolism, Vero Cells, Leishmania major drug effects, Thiosemicarbazones chemistry, Thiosemicarbazones pharmacology, Trypanocidal Agents chemistry, Trypanocidal Agents pharmacology
- Abstract
Leishmaniasis is a devastating tropical disease with limited therapeutic options. Depending on recently reported active anti-leishmanial compounds, we designed and synthesized a series of click modifiable 1,2,3-triazole and thiosemicarbazone hybrids. Most of the synthesized compounds showed comparable to superior activity to a well-established anti-leishmanial drug miltefosine. Compounds 2 and 10a showed nanomolar IC
50 s against promastigotes of L. major (227.4 nM and 140.3 nM respectively, vs 7.8 μM for miltefosine). Their antiamastigote IC50 s were 1.4 μM and 1 μM respectively, which are 6 and 8 times the activity of miltefosine (IC50 8.09 μM). Folic and folinic acids reversed the anti-leishmanial effects of compounds 2 and 10a and hence we anticipate they act via an anti-folate mechanism. They exhibited better safety profiles than that of miltefosine on VERO cell lines. Also they were relatively safe on experimental mice when administered via oral and parenteral routes. Docking experiments on PTR1 identified preferential binding interactions and docking scores. Finally, drug-likeness and ligand efficiency were assessed indicating that both 2 and 10a are promising hits and/or leads as anti-leishmanial chemotherapeutic agents., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)- Published
- 2018
- Full Text
- View/download PDF
18. Novel click modifiable thioquinazolinones as anti-inflammatory agents: Design, synthesis, biological evaluation and docking study.
- Author
-
Moussa G, Alaaeddine R, Alaeddine LM, Nassra R, Belal ASF, Ismail A, El-Yazbi AF, Abdel-Ghany YS, and Hazzaa A
- Subjects
- Animals, Anti-Inflammatory Agents, Non-Steroidal chemical synthesis, Anti-Inflammatory Agents, Non-Steroidal chemistry, Arachidonate 15-Lipoxygenase metabolism, Cell Differentiation drug effects, Click Chemistry, Cyclooxygenase 1 metabolism, Cyclooxygenase 2 metabolism, Cyclooxygenase Inhibitors chemical synthesis, Cyclooxygenase Inhibitors chemistry, Dose-Response Relationship, Drug, Female, Humans, Lipoxygenase Inhibitors chemical synthesis, Lipoxygenase Inhibitors chemistry, Macrophages drug effects, Molecular Docking Simulation, Molecular Structure, Quinazolinones chemical synthesis, Quinazolinones chemistry, Rats, Rats, Wistar, Structure-Activity Relationship, Sulfhydryl Compounds chemical synthesis, Sulfhydryl Compounds chemistry, Tumor Cells, Cultured, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Cyclooxygenase Inhibitors pharmacology, Drug Design, Lipoxygenase Inhibitors pharmacology, Quinazolinones pharmacology, Sulfhydryl Compounds pharmacology
- Abstract
Click chemistry was used to synthesize a new series of thioquinazolinone molecules equipped with propargyl moiety,1,2,3-triazolyl and isoxazolyl rings. Our design was based on merging pharmacophores previously reported to exhibit COX-2 inhibitory activities to a thioquinazolinone-privileged scaffold. The synthesized compounds were subjected to in vitro cyclooxygenase COX-1/COX-2 and 15-LOX inhibition assays. Compounds 2c, 3b, 3h, 3j, and 3k showed COX-2 inhibition with IC
50 (μM) 0.18, 0.19, 0.11, 0.16 and 0.17 respectively. These values were compared to celecoxib (IC50 0.05 μM), diclofenac (IC50 0.8 μM) and indomethacin (IC50 0.49 μM) reference drugs. They also showed 15-LOX inhibition with IC50 (μM) 6.21, 4.33, 7.62, 5.21 and 3.98 respectively. These values were compared with Zileuton (IC50 2.41 μM) and Meclofenamate sodium (IC50 5.64 μM) as positive controls. These compounds were further challenged by PMA-induced THP-1 differentiation assay where compounds 2c and 3j inhibited monocyte to macrophage differentiation efficiently with IC50 values of 4.78 μM and 5.63 μM, respectively, compared to that of diclofenac sodium (4.86 μM). On the other hand, 3h demonstrated a significantly increased potency compared to diclofenac in this assay (IC50 = 0.13 μM). The same compounds exhibited significant in vivo anti-inflammatory effect as indicated by the formalin-induced rat-paw edema test. Docking experiments of compounds 2c, 3b, 3h, 3j, and 3k into COX-2 binding pocket have been conducted, where strong binding interactions have been identified and effective overall docking scores have been recorded. Their drug-likeness has been assessed using Molinspiration, Molsoft and Pre-ADMET software products., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)- Published
- 2018
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.