Publications by authors named "Ahmed Belal"

17 Publications

  • Page 1 of 1

Challenging inflammatory process at molecular, cellular and in vivo levels via some new pyrazolyl thiazolones.

J Enzyme Inhib Med Chem 2021 Dec;36(1):669-684

Department of Pharmacology and Toxicology, Faculty of Medicine and Medical Centre, American University of Beirut, Beirut, Lebanon.

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 (IC values of 0.09-0.14 µM) with significant 15-LOX inhibitory activities (ICs 1.96 to 3.52 µM). Upon investigation of their 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, predictions confirmed the appropriateness of these compounds as drug-like candidates.
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http://dx.doi.org/10.1080/14756366.2021.1887169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901699PMC
December 2021

Standardization of cerebrospinal fluid shunt valves in pediatric hydrocephalus: an analysis of cost, operative time, length of stay, and shunt failure.

J Neurosurg Pediatr 2021 Jan 29:1-6. Epub 2021 Jan 29.

Objective: CSF shunts are the most common procedures performed in the pediatric neurosurgical population. Despite attempts in multiple studies, a superior shunt valve has never been shown. Because of this, the authors aim was to examine the impact of shunt valve standardization at their institution to determine if there is a difference in surgical cost, operative time, or short-term postoperative shunt failure.

Methods: A retrospective analysis at the authors' institution was performed for all new CSF diversion shunts, as well as shunt revisions requiring a new valve, or a new valve and at least a new proximal or distal catheter over a 1-year period (January 1, 2016, to December 31, 2016). After a period of transition, neurosurgeons were encouraged to use only one type of fixed-differential-pressure valve and one type of programmable valve when performing shunt surgeries. These patients who underwent "standardized" shunt surgery over a 1-year period (January 1, 2018, to December 31, 2018) were then compared to patients in the prestandardization epoch. All patients were followed for a 12-month period after surgery. Demographic information, surgical cost, operative time, and postoperative shunt failure data were collected in all patients in the study.

Results: The authors analyzed 87 shunt surgeries in patients prior to standardization and 94 shunt surgeries in patients after standardization. The rate of violation of the standardized shunt valve policy after implementation was 5.3% (5 of 94 procedures). When comparing the prestandardization group to those who received the standardized valve, operative costs were less ($1821.04 vs $1333.75, p = 0.0034). There was no difference in operative times between groups (78 minutes vs 81 minutes, p = 0.5501). There was no difference in total number of shunt failures between the two groups at 12 months after surgery (p = 0.0859). The rate of postoperative infection was consistent with the literature at 8%.

Conclusions: In accordance with quality improvement principles, the reduction of unexplained clinical variance invariably leads to a decrease in cost and, more importantly, increased value. In this study, the implementation of a standardized shunt valve decreased operative cost. There were no differences in postoperative shunt failures at 12 months after surgery and no differences in length of surgery. Standardizing shunt valves in the treatment of pediatric hydrocephalus seems to be cost-effective and safe.
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http://dx.doi.org/10.3171/2020.8.PEDS20477DOI Listing
January 2021

Design and discovery of new 1,2,4-triazolo[4,3-c]quinazolines as potential DNA intercalators and topoisomerase II inhibitors.

Arch Pharm (Weinheim) 2021 Mar 23;354(3):e2000237. Epub 2020 Nov 23.

Pharmaceutical Medicinal Chemistry and Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.

A new series of 1,2,4-triazolo[4,3-c]quinazoline derivatives was designed and synthesized as Topo II inhibitors and DNA intercalators. The cytotoxic effect of the new members was evaluated in vitro against a group of cancer cell lines including HCT-116, HepG-2, and MCF-7. Compounds 14 , 14 , 14 , 14 , 15 , 18 , 18 , and 19 exhibited the highest activities with IC values ranging from 5.22 to 24.24 µM. Furthermore, Topo II inhibitory activities and DNA intercalating affinities of the most promising candidates were evaluated as a possible mechanism for the antiproliferative effect. The results of the Topo II inhibition and DNA binding tests were coherent with that of in vitro cytotoxicity. Additionally, the most promising compound 18 was analyzed in HepG-2 cells for its apoptotic effect and cell cycle arrest. It was found that 18 can induce apoptosis and arrest the cell cycle at the G2-M phase. Finally, molecular docking studies were carried out for the designed compounds against the crystal structure of the DNA-Topo II complex as a potential target to explore their binding modes. On the basis of these studies, it was hypothesized that the DNA binding and/or Topo II inhibition would participate in the noted cytotoxicity of the synthesized compounds.
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http://dx.doi.org/10.1002/ardp.202000237DOI Listing
March 2021

The emerging role of COX-2, 15-LOX, and PPARγ in metabolic diseases and cancer: An introduction to novel multi-target directed ligands (MTDLs).

Curr Med Chem 2020 Aug 20. Epub 2020 Aug 20.

Department of Pharmacology and Toxicology, Faculty of Medicine, The American University of Beirut, Beirut. Lebanon.

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 anti-tumorigenic 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 summarize 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.
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http://dx.doi.org/10.2174/0929867327999200820173853DOI Listing
August 2020

Expanding the anticancer potential of 1,2,3-triazoles via simultaneously targeting Cyclooxygenase-2, 15-lipoxygenase and tumor-associated carbonic anhydrases.

Eur J Med Chem 2020 Aug 25;200:112439. Epub 2020 May 25.

Università, Degli Studi di Firenze, NEUROFARBA Dept, Sezione di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019, Sesto Fiorentino, Florence, Italy. Electronic address:

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 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.
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http://dx.doi.org/10.1016/j.ejmech.2020.112439DOI Listing
August 2020

Dosing parameters for the effects of high-frequency transcranial magnetic stimulation on smoking cessation: study protocol for a randomized factorial sham-controlled clinical trial.

BMC Psychol 2020 May 1;8(1):42. Epub 2020 May 1.

Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14203, USA.

Background: Despite the considerable success of comprehensive tobacco control efforts, tobacco use remains one of the greatest preventable causes of death and disease today. Over half of all smokers in the US make quit attempts every year, but over 90% relapse within 12 months, choosing the immediate reinforcement of smoking over the long-term benefits of quitting. Conceptual and empirical evidence supports continued investigation of high frequency repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex in reducing relapse and decreasing cigarette consumption. While this evidence is compelling, an optimal dosing strategy must be determined before a long-term efficacy trial can be conducted. The goal of this study is to determine a dosing strategy for 20 Hz rTMS that will produce the best long-term abstinence outcomes with the fewest undesirable effects.

Methods: This is a fully crossed, double-blinded, sham-controlled, 3x2x2 randomized factorial study. The three factors are duration (stimulation days: 8, 12, and 16); intensity (900 or 1800 pulses per day); and sham control. Participants (n = 258) will consist of adults (18-65) who are motivated to quit smoking cigarettes and who will be followed for 6 months post-quit. Outcomes include latency to relapse, point prevalence abstinence rates, delay discounting rates, cognitive-behavioral skills acquisition, and multiple measures of potential undesirable effects that impact participant compliance.

Discussion: This study integrates existing theoretical concepts and methodologies from neuropsychology, behavioral economics, brain stimulation, clinical psychology, and the evidence-based treatment of tobacco dependence in the development of a promising and innovative approach to treat tobacco dependence. This study will establish an optimal dosing regimen for efficacy testing. Findings are expected to have a significant influence on advancing this approach as well as informing future research on clinical approaches that combine rTMS with other evidence-based treatments for tobacco dependence and perhaps other addictions.

Trial Registration: Clinical Trials NCT03865472 (retrospectively registered). The first participant was fully enrolled on November 26, 2018. Registration was posted on March 7, 2019.
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http://dx.doi.org/10.1186/s40359-020-00403-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193364PMC
May 2020

Bioconjugation in Drug Delivery: Practical Perspectives and Future Perceptions.

Methods Mol Biol 2019 ;2000:125-182

Department of Pharmaceutical Sciences, School of Pharmacy & Physician Assistant Studies (SOPPAS), University of Saint Joseph (USJ), Hartford, CT, USA.

For the past three decades, pharmaceutical research has been mainly converging to novel carrier systems and nanoparticulate colloidal technologies for drug delivery, such as nanoparticles, nanospheres, vesicular systems, liposomes, or nanocapsules to impart novel functions and targeting abilities. Such technologies opened the gate towards more sophisticated and effective multi-acting platform(s) which can offer site-targeting, imaging, and treatment using a single multifunctional system. Unfortunately, such technologies faced major intrinsic hurdles including high cost, low stability profile, short shelf-life, and poor reproducibility across and within production batches leading to harsh bench-to-bedside transformation.Currently, pharmaceutical industry along with academic research is investing heavily in bioconjugate structures as an appealing and advantageous alternative to nanoparticulate delivery systems with all its flexible benefits when it comes to custom design and tailor grafting along with avoiding most of its shortcomings. Bioconjugation is a ubiquitous technique that finds a multitude of applications in different branches of life sciences, including drug and gene delivery applications, biological assays, imaging, and biosensing.Bioconjugation is simple, easy, and generally a one-step drug (active pharmaceutical ingredient) conjugation, using various smart biocompatible, bioreducible, or biodegradable linkers, to targeting agents, PEG layer, or another drug. In this chapter, the different types of bioconjugates, the techniques used throughout the course of their synthesis and characterization, as well as the well-established synthetic approaches used for their formulation are presented. In addition, some exemplary representatives are outlined with greater emphasis on the practical tips and tricks of the most prominent techniques such as click chemistry, carbodiimide coupling, and avidin-biotin system.
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http://dx.doi.org/10.1007/978-1-4939-9516-5_11DOI Listing
March 2020

Shooting three inflammatory targets with a single bullet: Novel multi-targeting anti-inflammatory glitazones.

Eur J Med Chem 2019 Apr 13;167:562-582. Epub 2019 Feb 13.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt. Electronic address:

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 values) and moderate 15-LOX inhibitor (micromolar IC 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.
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http://dx.doi.org/10.1016/j.ejmech.2019.02.034DOI Listing
April 2019

Tackling neuroinflammation and cholinergic deficit in Alzheimer's disease: Multi-target inhibitors of cholinesterases, cyclooxygenase-2 and 15-lipoxygenase.

Eur J Med Chem 2019 Apr 8;167:161-186. Epub 2019 Feb 8.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ejmech.2019.02.012DOI Listing
April 2019

Radiofrequency Ablation and Radiation Therapy Improve Local Control in Spinal Metastases Compared to Radiofrequency Ablation Alone.

Am J Hosp Palliat Care 2019 May 13;36(5):417-422. Epub 2018 Dec 13.

2 Department of Radiology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

Purpose:: The spinal column is the most common location for osseous metastases and is associated with pain and decreased quality of life. This study evaluated combined radiofrequency ablation (RFA) with radiation therapy (RT) compared to RFA alone for improving pain and local control.

Methods:: This was a single-institution retrospective review of patients who underwent RFA of spinal metastases between 2016 and 2017, with or without RT to the same vertebral level. Pain was measured with visual analog scale at initial presentation and at 3 and 12 weeks of follow-up. Local failure (LF), distant failure, and overall survival (OS) were compared and Kaplan-Meier statistics were calculated.

Results:: Twenty-six patients with 28 spinal metastases were treated with RFA. Ten patients with 11 metastases were treated with RFA + RT. More patients with lung primaries were treated with RFA alone and more patients with breast primaries were treated with combination RFA+RT. There was no significant difference in pain scores between groups ( P = .96). At a median follow-up of 8.2 months, LF was noted in 8 of 17 metastases treated with RFA alone compared to 1 of 11 metastases treated with RFA+RT ( P = .049). There was a significant benefit in time to LF favoring RFA+RT ( P = .02) and a significant benefit in OS ( P = .0045).

Conclusion:: This study demonstrates a benefit in local control with RFA+RT versus RFA alone. Palliation of pain was effective using both regimens. This study was limited by a nearly unequal distribution of primary tumor histologies between groups. Literature regarding combined treatment of RFA and RT for spinal metastases is scarce and prospective protocols are warranted.
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http://dx.doi.org/10.1177/1049909118819460DOI Listing
May 2019

Click chemistry inspired copper sulphide nanoparticle-based fluorescence assay of kanamycin using DNA aptamer.

Spectrochim Acta A Mol Biomol Spectrosc 2018 Dec 7;205:48-54. Epub 2018 Jul 7.

Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.

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 = 365 nm, λ = 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.
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http://dx.doi.org/10.1016/j.saa.2018.07.011DOI Listing
December 2018

Variable Asymmetric Chains in Transition Metal Oxyfluorides: Structure-Second-Harmonic-Generation Property Relationships.

Inorg Chem 2018 Jun 15;57(11):6702-6709. Epub 2018 May 15.

Department of Chemistry , Chung-Ang University , 84 Heukseok-ro, Dongjak-gu , Seoul 06974 , Republic of Korea.

Four novel transition metal oxyfluorides, [Zn(pz)][MoOF]·0.1HO (1), [Zn(pz)F][Zn(pz)][WOF] (2), [Cd(pz)][Cd(pz)(HO)][MoOF]·0.625HO (3), and [Zn(mpz)][MoOF] (4) (pz = pyrazole; mpz = 3-methyl pyrazole) have been synthesized. Compounds 1 and 4 contain helical chains. Compound 2 accommodates zigzag chains, and compound 3 has quasi-one-dimensional linear chains. The variable chain structures are found to be attributable to the different structure-directing anionic groups and hydrogen bonding interactions. Compound 4 crystallized in the noncentrosymmetric (NCS) polar space group, Pna2, is nonphase-matchable (Type I), and reveals a moderate second-harmonic-generation (SHG) efficiency (10 × α-SiO). The observed SHG efficiency of compound 4 is due to the small net polarization occurring from the arrangement of ZnNF trigonal bipyramids. Spectroscopic and thermal characterizations along with calculations for the title materials are reported.
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http://dx.doi.org/10.1021/acs.inorgchem.8b00903DOI Listing
June 2018

Anti-leishmanial click modifiable thiosemicarbazones: Design, synthesis, biological evaluation and in silico studies.

Eur J Med Chem 2018 May 3;151:585-600. Epub 2018 Apr 3.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt. Electronic address:

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 ICs against promastigotes of L. major (227.4 nM and 140.3 nM respectively, vs 7.8 μM for miltefosine). Their antiamastigote ICs were 1.4 μM and 1 μM respectively, which are 6 and 8 times the activity of miltefosine (IC 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.
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http://dx.doi.org/10.1016/j.ejmech.2018.04.003DOI Listing
May 2018

Novel click modifiable thioquinazolinones as anti-inflammatory agents: Design, synthesis, biological evaluation and docking study.

Eur J Med Chem 2018 Jan 18;144:635-650. Epub 2017 Dec 18.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.

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 (μM) 0.18, 0.19, 0.11, 0.16 and 0.17 respectively. These values were compared to celecoxib (IC 0.05 μM), diclofenac (IC 0.8 μM) and indomethacin (IC 0.49 μM) reference drugs. They also showed 15-LOX inhibition with IC (μM) 6.21, 4.33, 7.62, 5.21 and 3.98 respectively. These values were compared with Zileuton (IC 2.41 μM) and Meclofenamate sodium (IC 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 IC 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 (IC = 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.
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http://dx.doi.org/10.1016/j.ejmech.2017.12.065DOI Listing
January 2018

Clinical study of a survivin long peptide vaccine (SurVaxM) in patients with recurrent malignant glioma.

Cancer Immunol Immunother 2016 11 30;65(11):1339-1352. Epub 2016 Aug 30.

Department of Biostatistics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA.

Survivin is an anti-apoptotic protein that is highly expressed in many cancers, including malignant gliomas. Preclinical studies established that the conjugated survivin peptide mimic SurVaxM (SVN53-67/M57-KLH) could stimulate an anti-tumor immune response against murine glioma in vivo, as well as human glioma cells ex vivo. The current clinical study was conducted to test safety, immunogenicity and clinical effects of the vaccine. Recurrent malignant glioma patients whose tumors were survivin-positive, and who had either HLA-A*02 or HLA-A*03 MHC class I allele-positivity, were given subcutaneous injections of SurVaxM (500 μg) in Montanide ISA 51 with sargramostim (100 μg) at 2-week intervals. SurVaxM was well tolerated with mostly grade one adverse events (AE) and no serious adverse events (SAE) attributable to the study drug. Six patients experienced local injection site reactions; three patients reported fatigue (grades 1 and 2), and 2 patients experienced myalgia (grade 1). Six of eight immunologically evaluable patients developed both cellular and humoral immune responses to vaccine. The vaccine also stimulated HLA-A*02, HLA-A*03 and HLA-A*24 restricted T cell responses. Three patients maintained a partial clinical response or stable disease for more than 6 months. Median progression-free survival was 17.6 weeks, and median overall survival was 86.6 weeks from study entry with seven of nine patients surviving more than 12 months.
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http://dx.doi.org/10.1007/s00262-016-1890-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5069322PMC
November 2016

Diagnostic Value of Magnetic Resonance Spectroscopy Compared with Stereotactic Biopsy of Intra-axial Brain Lesions.

J Neurol Surg A Cent Eur Neurosurg 2016 Jul 2;77(4):283-90. Epub 2016 Mar 2.

Department of Diagnostic Radiology, Alexandria University, Alexandria, Egypt.

Background Magnetic resonance spectroscopy (MRS) is usually added to conventional magnetic resonance imaging (MRI) to refine the diagnosis of different brain lesions. Stereotactic brain biopsy is a well-established method to obtain tissues for histopathologic examination. The purpose of the study is to compare the diagnostic yields of MRS and stereotactic biopsy in the characterization of brain lesions. Material and Methods A prospective study conducted on 27 consecutive patients presenting with multifocal, diffuse, as well as deeply seated intra-axial brain lesions. All patients had both brain MRI and MRS prior to stereotactic biopsy. Histopathologic examinations of the obtained tissue specimens, using appropriate stains including immunostains, were performed. Results MRS diagnosed neoplastic brain lesions in 15 cases (56%) and nonneoplastic brain lesions in 12 (44%). Correlation between the preoperative diagnosis by MRS and the histopathologic diagnosis following stereotactic biopsy of either a neoplastic or nonneoplastic lesion revealed matching in 25 of 27 cases (sensitivity 88%; specificity 100%). Within the group of cases (n = 15) diagnosed preoperatively by MRS as neoplastic, 12 patients were diagnosed with brain gliomas of different grades. The MRS grading of gliomas exactly matched the histopathologic grading following stereotactic biopsy in 10 of the 12 cases (sensitivity 89%; specificity 67%). Conclusions MRS is a useful addition to the management armamentarium, providing molecular information that assists in the characterization of various brain lesions. Multivoxel MRS may increase the diagnostic yield of stereotactic biopsy by guidance to target the higher choline and lower N-acetylaspartate areas, expected to have greater tumor activity.
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http://dx.doi.org/10.1055/s-0035-1571162DOI Listing
July 2016

Optimization of a genetically encoded biosensor for cyclin B1-cyclin dependent kinase 1.

Mol Biosyst 2014 Feb;10(2):191-5

Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, Canada.

Fluorescent protein (FP)-based biosensors have revolutionized the ability of researchers to monitor enzyme activities in live cells. While the basic design principles for FP-based biosensors are well established, first-generation biosensor constructs typically suffer from relatively low fluorescence responses that limit their general applicability. The protein engineering efforts required to substantially improve the biosensor responses are often both labour and time intensive. Here we report the application of a high throughput bacterial colony screen for improving the response of kinase biosensors. This effort led to the development of a second-generation cyclin B1-CDK1 biosensor with a 4.5-fold greater response than the first-generation biosensor.
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http://dx.doi.org/10.1039/c3mb70402eDOI Listing
February 2014