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A series of triazole-tethered triazines bearing pharmacophoric features of DNA-targeting agents and non-hydroxamate MMPs inhibitors were synthesized and screened against HCT-116, Caco-2 cells, and normal colonocytes by MTT assay. 7a and 7g surpassed doxorubicin against HCT-116 cells regarding potency (IC 50 = 0.87 and 1.41 nM) and safety (SI = 181.93 and 54.41). 7g was potent against liver cancer (HepG-2; IC 50 = 65.08 nM), the main metastatic site of CRC with correlation to MMP-13 expression. Both derivatives induced DNA damage at 2.67 and 1.87 nM, disrupted HCT-116 cell cycle and triggered apoptosis by 33.17% compared to doxorubicin (DNA damage at 0.76 nM and 40.21% apoptosis induction). 7g surpassed NNGH against MMP-10 (IC 50 = 0.205 μM) and MMP-13 (IC 50 = 0.275 μM) and downregulated HCT-116 VEGF related to CRC progression by 38%. Docking and MDs simulated ligands-receptors binding modes and highlighted SAR. Their ADMET profiles, drug-likeness and possible off-targets were computationally predicted.

Non-small cell lung cancer (NSCLC) continues to be a leading cause of cancer death. Its fatality is associated with angiogenesis and metastasis. While VEGFR inhibitors are expected to be the central pillar for halting lung cancer, several clinical reports declared their subpar activities as monotherapy. These results directed combination studies of VEGFR inhibitors, especially sorafenib (Nexavar®), with various chemotherapeutic agents. Matrix metalloproteinase (MMP) inhibitors are seldom utilized in such combinations despite the expected complementary therapeutic outcome. This could be attributed to the clinical unsuitability of MMP inhibitors from the hydroxamate family. Herein, we report new non-hydroxamate s-triazinedione-based inhibitors of MMP-9 (6b; IC 50  = 0.112 μM), and MMP-10 (6e; IC 50  = 0.076 μM) surpassing the hydroxamate inhibitor NNGH for chemosensitization of NSCLC to sorafenib. MMPs inhibition profiling of the hits revealed MMP-9 over -2 and MMP-10 over -13 selectivity. 6b and 6e were potent (IC 50  = 0.139 and 0.136 µM), safe (SI up to 6.77) and superior to sorafenib (IC 50  = 0.506 µM, SI = 6.27) against A549 cells. When combined with sorafenib, the studied MMP inhibitors enhanced its cytotoxic efficacy up to 26 folds as confirmed by CI and DRI values for 6b (CI = 0.160 and DRI = 22.175) and 6e (CI = 0.096 and DRI = 29.060). 6b and 6e exerted anti-invasive activities in A549 cells as single agents (22.66 and 39.67 %) and in sorafenib combinations (29.96 and 91.83 %) compared to untreated control. Both compounds downregulated VEGF in A549 cells by approximately 70 % when combined with sorafenib, highlighting enhanced anti-angiogenic activities. Collectively, combinations of 6b and 6e with sorafenib demonstrated synergistic NSCLC cytotoxicity with pronounced anti-invasive and anti-angiogenic activities introducing a promising start point for preclinical studies., 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 Elsevier Inc. All rights reserved.)

There is an increasing interest in halting CRC by combining ferroptosis with other forms of tumor cell death. However, ferroptosis induction is seldom studied in tandem with inhibiting MMPs. A combination that is expected to enhance the therapeutic outcome based on mechanistic ferroptosis studies highlighting the interplay with MMPs, especially MMP-13 associated with CRC metastasis and poor prognosis. Herein, we report new hybrid triazines capable of simultaneous MMP-10/13 inhibition and ferroptosis induction bridging the gap between their anticancer potentials. The MMP-10/13 inhibitory component of the scaffold was based on the non-hydroxamate model inhibitors. s-Triazine was rationalized as the core inspired by altretamine, an FDA-approved ferroptosis inducer. The ferroptosis pharmacophores were then installed as Michael acceptors via triazole-based spacers. The electrophilic reactivity was tuned by incorporating cyano and/or substituted phenyl groups influencing their electronic and steric properties and enriching the SAR study. Initial screening revealed the outstanding cytotoxicity profiles of the nitrophenyl-tethered chalcone 5e and the cyanoacrylohydrazides bearing p-fluorophenyl 9b and p-bromophenyl 9d appendages. 9b and 9d surpassed NNGH against MMP-10 and -13, especially 9d (IC 50  = 0.16 μM). Ferroptosis studies proved that 9d depleted GSH in HCT-116 cells by a relative fold decrement of 0.81 with modest direct GPX4 inhibition, thus inducing lipid peroxidation, the hallmark of ferroptosis, by 1.32 relative fold increment. Docking presumed that 9d could bind to the MMP-10 S1' pocket and active site His221, extend through the MMP-13 hydrophobic pocket, and interact covalently with the GPX4 catalytic selenocysteine. 9d complexed with ferrous oxide nanoparticles was 7.5 folds more cytotoxic than its free precursor against HCT-116 cells. The complex-induced intracellular iron overload, depleted GSH with a relative fold decrement of 0.12, consequently triggering lipid peroxidation and ferroptosis by a 3.94 relative fold increment. Collectively, 9d could be a lead for tuning MMPs selectivity and ferroptosis induction potential to maximize the benefit of such a combination., 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 Inc. All rights reserved.)

A novel thiourea derivative has been successfully synthesized via green routes and fully characterized by FT-IR, 1 H, 13 C-NMR, and elemental analysis. The synthetic inhibitor 2-amino- N -(phenylcarbamothioyl) benzamide (APCB) was assessed as a corrosion inhibitor for mild steel (MS) in 0.5 M H 2 SO 4 . Various electrochemical techniques, such as electrochemical impedance spectroscopy (EIS) and potentiodynamic polarization (PDP), have been used to evaluate inhibition efficiency. As a result, EIS and PDP agreed with each other, indicating that APCB exhibits an inhibition performance that exceeds 96% at a concentration of 2 × 10 -4 M and increases with an increase in temperature up to 98% at 333 K. However, PDP measurements showed that APCB is a mixed type of inhibitor. In addition, SEM, EDX, AFM, and contact angle measurements were used as a topological surface characterization technique that confirmed the formation of a protective layer over the MS surface. Additionally, the complex formation was thoroughly confirmed by UV-Vis measurements. The adsorption of APCB proved the highest compliance with the Langmuir adsorption isotherm. Furthermore, density functional theory (DFT) calculations were conducted to establish the correlation between the electronic structure and excellent inhibition efficiency. Moreover, molecular dynamics (MD) simulations were used to find interaction energy in different media. Finally, the adsorption affinity of the MS surface for different concentrations of APCB was verified via Monte Carlo (MC) simulations. Owing to the outcomes of this study, it is remarkable that APCB, with its low cost and simple synthesis, might be an exceptionally prominent option for mild steel protection.

Off-target side effects are major challenges hindering the clinical success of matrix metalloproteinase (MMP) inhibitors. Various targeting strategies revitalized MMP research to eliminate this drawback. Herein, we developed s -triazine-based dendrimeric architecture not only amenable to tumor targeting but also decorated with pharmacophoric entities to endow MMP-9 inhibition for halting cancer progression. The design rationale utilized hydrazide branching chains as well as carboxylic and hydroxamic acid termini as Zn-binding groups to confer substantial MMP inhibitory potential. The carboxylic acids are tetherable to tumor targeting ligands and other cargo payloads as synergistic drugs via biodegradable linkages. The synthesized series were screened for cytotoxicity against normal fibroblasts (Wi-38) and two selected cancers (MDA-MB 231 and Caco-2) via MTT assay. The most active hexacarboxylic acid dendrimer 8a was more potent and safer than Dox against MDA-MB 231 and Caco-2 cells. It intrinsically inhibited MMP-9 with selectivity over MMP-2. Docking simulations demonstrated that the extended carboxylic acid termini of 8a could possibly chelate the active site Zn of MMP-9 and form hydrogen-bonding interactions with the ligand essential backbone Tyr423. In addition, it suppressed the correlated oncogenic mediators VEGF and cyclin D, upregulated p21 expression, induced apoptosis (>75%), and inhibited the tumor cell migration (∼84%) in the treated cancer cells. Thus, up to our knowledge, it is the first triazine-based MMP-9 inhibitor dendrimer endowed with VEGF suppression potential that can be employed as a bioactive carrier., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Plastic pollution and its impact on marine ecosystems are major concerns globally, and the situation was exacerbated after the outbreak of COVID-19. Clean-up campaigns took place during the summer season (June-August 2020) in two coastal cities in Egypt (Alexandria and Hurghada) and Jeddah, Saudi Arabia to document the abundance of beach debris through public involvement, and then remove it. A total of 3673, 255, and 848 items were collected from Alexandria, Hurghada, and Jeddah daily, respectively. Gloves and face masks (personal protective equipment "PPE") represent represented 40-60% of the total plastic items collected from each of the three cities, while plastic bags represented 7-20% of the total plastics litter collected from the same cities. The results indicated the presence of 2.79, 0.29, and 0.86 PPE item m -2 in Alexandria, Hurghada and Jeddah, respectively. This short focus provides an assessment of the environmental impacts of single-use gloves and masks used for COVID-19 protection from June to August 2020. To the best of our knowledge, this study presents the first such information from the Middle East, specifically Egypt and Saudi Arabia. It highlights the need for further knowledge and action, such as safe, sustainable, and transparent waste management processes related to COVID-19 to reduce the negative impacts now, as well as in future events. Furthermore, this study helps in achieving key components of the United Nation's Sustainable Development Goals (SDGs). This short focus can serve as a multipurpose document, not only for scientists of different disciplines but for social media and citizens in general., Competing Interests: Declaration of competing interest We believe this subject is interesting and no data were published from Egypt or Saudi Arabia. We have the pleasure to submit this paper as a short communication. Having said that, I could not find a short communication option regarding the submission, so I have selected the nearest option. The authors declare no potential conflicts of interest concerning the research, authorship, and/or publication of this article., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Despite the advances in developing MMP-2/9 inhibitors, off-target side effects and pharmacokinetics problems remain major challenges hindering their clinical success in cancer therapy. However, recent targeting strategies have clearly revitalized MMP research. Herein, we introduce new s-triazine-based dendrimers endowed with intrinsic MMP-2/9 inhibitory potential and tetherable to hepatocellular carcinoma-specific targeting ligands and anticancer agents via biodegradable linkages for targeted therapy. The designed dendrimeric platform was built with potential zinc-binding branching linkers (hydrazides) and termini (carboxylic acids and hydrazides) to confer potency against MMP-2/9. Preliminary cytotoxicity screening and MMP-2/9 inhibition assay of the free dendrimers revealed promising potency (MMP-9; IC 50 =0.35-0.57 μM, MMP-2; IC 50 =0.39-0.77 μM) within their safe doses (EC 100 =94.15-42.75 μM). The hydrazide dendrimer was comparable to NNGH and superior to the carboxylic acid analogue. MTT assay showed that the free dendrimers were superior to the reference anticancer agent honokiol. Their anticancer potency was enhanced by HK conjugation, targeting ligands installation and PEGylation as exemplified by the hydrazide dendrimer conjugate (TPG 3 -NH 2 )-SuHK-FA-SuPEG (Huh-7; IC 50 =5.54 μM, HepG-2; IC 50 =10.07 μM) being 4 folds more active than HK, followed by the carboxylic acid conjugate (TPG 3 -OH)-HK-LA-PEG (Huh-7; IC 50 =14.97, HepG-2; IC 50 =21.29 μM). This was consistent with apoptosis studies., (© 2021 Wiley-VCH GmbH.)

Despite the active research towards introducing novel anticancer agents, the long-term sequelae and side effects of chemotherapy remain the major obstacle to achieving clinical success. Recent cancer research is now utilizing the medicinal chemistry toolbox to tailor novel 'smart' carrier systems that can reduce the major limitations of chemotherapy ranging from non-specificity and ubiquitous biodistribution to systemic toxicity. In this aspect, various stimuli-responsive polymers have gained considerable interest due to their intrinsic tumor targeting properties. Among these polymers, poly(N-isopropylacrylamide (PNIPAM) has been chemically modified to tune its thermoresponsivity or even copolymerized to endow new stimulus responsiveness for enhancing tumor targeting. Herein, we set our design rationale to impart additional active targeting entity to pH/temperature-responsive PNIPAM-based polymer for more efficient controlled payloads accumulation at the tumor through cellular internalization via synthesizing novel "super intelligent" lactoferrin conjugated PNIPAM-acrylic acid (LF-PNIPAM-co-AA) copolymer. The synthesized copolymer was physicochemically characterized and evaluated as a smart nanocarrier for targeting breast cancer. In this regard, Honokiol (HK) was utilized as a model anticancer drug and encapsulated in the nanoparticles to overcome its lipophilic nature and allow its parenteral administration, for achieving sustainable drug release with targeting action. Results showed that the developed HK-loaded LF-PNIPAM-co-AA nanohydrogels displayed high drug loading capacity reaching to 18.65 wt.% with excellent physical and serum stability. Moreover, the prepared HK-loaded nanohydrogels exhibited efficient in vitro and in vivo antitumor activities. In vivo, HK-loaded nanohydrogels demonstrated suppression of VEGF-1 and Ki-67 expression levels, besides inducing apoptosis through upregulating the expression level of active caspase-3 in breast cancer-bearing mice. Overall, the developed nanohydrogels (NGs) with pH and temperature responsivity provide a promising nanocarrier for anticancer treatment., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Breast cancer is not only one of the most prevalent types of cancer, but also it is a prime cause of death in women aged between 20 and 59. Although chemotherapy is the most common therapy approach, multiple side effects can result from lack of specificity and the use of overdose as safe doses may not completely cure cancer. Therefore, we aimed in this study is to combine the merits of NF-κB inhibiting potential of celastrol (CST) with glutathione inhibitory effect of sulfasalazine (SFZ) which prevents CST inactivation and thus enhances its anti-tumor activity. Inspired by the CD44-mediated tumor targeting effect of the hydrophilic polysaccharide chondroitin sulphate (ChS), we chemically synthesized amphiphilic zein-ChS micelles. While the water insoluble SFZ was chemically coupled to zein, CST was physically entrapped within the hydrophobic zein/SFZ micellar core. Moreover, physical encapsulation of oleic acid-capped SPIONs in the hydrophobic core of micelles enabled both magnetic tumor targeting as well as MRI theranostic capacity. Combining magnetic targeting to with the active targeting effect of ChS resulted in enhanced cellular internalization of the micelles in MCF-7 cancer cells and hence higher cytotoxic effect against MCF-7 and MDA-MB-231 breast cancer cells. In the in vivo experiments, magnetically-targeted micelles (154.4 nm) succeeded in achieving the lowest percentage increase in the tumor volume in tumor bearing mice, the highest percentage of tumor necrosis associated with significant reduction in the levels of TNF-α, Ki-67, NF-κB, VEGF, COX-2 markers compared to non-magnetically targeted micelles-, free drug-treated and positive control groups. Collectively, the developed magnetically targeted micelles pave the way for design of cancer nano-theranostic drug combinations., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Three novel series of s-triazine derivatives, including thirty-five new compounds 2a-d, 3a-3p, 4b-d, 5b-d, 6d-6d, and 7a-7f were synthesized comprising a diversity of substituents based on the structure of Astrazeneca arylaminotriazine DNA gyrase B inhibitor. The antimicrobial activity was determined for all compounds against Staphylococcus aureus, Escherichia coli and Candida albicans using the two-fold serial dilution technique and against reference standards Ampicillin for the antibacterial screening and Clotrimazole regarding the antifungal evaluation. The tested compounds showed strong to moderate antibacterial inhibitory action and weak antifungal activity. Compounds 3j and 6b were the most potent antibacterial agents against the tested strains and multi-drug resistant (MDR) clinical isolates of Klebsiella pneumoniae and methicillin resistant Staphylococcus aureus (MRSA1) with minimal toxicity in comparison to the reference drugs. In silico molecular properties calculations and molecular docking study for 3j and 6b revealed that both compounds could be considered as promising antibacterial DNA gyrase B inhibitors., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A new small library of 2-aminobenzoyl amino acid hydrazide derivatives and quinazolinones derivatives was synthesized and fully characterized by IR, NMR, and elemental analysis. The activity of the prepared compounds on the growth of Leishmania aethiopica promastigotes was evaluated. 2-Benzoyl amino acid hydrazide showed higher inhibitory effect than the quinazoline counterpart. The in vitro antipromastigote activity demonstrated that compounds 2a, 2b, 2f and 4a had IC 50 better than standard drug miltefosine and comparable activity to amphotericin B deoxycholate, which indicates their high antileishmanial activity against Leishmania. aethiopica. Among the prepared compounds; 2-amino-N-(6-hydrazinyl-6-oxohexyl)benzamide 2f (IC 50 =0.051μM) has the best activity, 154 folds more active than reference standard drug miltefosine (IC 50 =7.832μM), and half fold the activity of amphotericin B (IC 50 =0.035μM). In addition, this compound was safe and well tolerated by experimental animals orally up to 250mg/kg and parenterally up to 100mg/kg., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The antiozonant chemical, ethylenediurea (N-[2-(2-oxo-1-imidazolidinyl)ethyl]-N'-phenylurea, abbreviated as EDU), was applied as stem injections or soil drenches to 5-year-old containerized plants of olive (Olea europaea L. cultivar Kalamata) in growth chambers in order to assess its ameliorative effects against realistic ozone (O3) stress. Visible injury symptoms were reduced greatly in individuals treated with EDU, with injection applications having greater protection than soil drenches. EDU application caused increases in the measured ecophysiological parameters compared to untreated individuals. In particular, the stem injection protected plants against photosynthetic impairment (unchanged net photosynthetic rates and intercellular CO2 concentration, in comparison to plants grown in filtered air). EDU application increased the protection of PSII from ambient O3 oxidative stress, although it did not retain the proportion of redox state of QA, pigment composition of photosynthetic apparatus and size of light-harvesting complex of PSII. However, the stem injection of plants with EDU induced lower non-photochemical quenching (NPQ) values in comparison to ambient air (-2 %), indicating a better photoprotection of PSII in comparison to soil drench application. EDU application caused increases in the morphological and biometric parameters compared to individuals exposed to ambient air. To the best of our knowledge, this is the first study highlighting the protection of Kalamata olive trees due to EDU in terms of growth, yield, visible injury, and photosynthetic performance. Furthermore, this study proved that EDU could be a low-cost and a low-technology efficient tool for assessing O3 effects on plant performances in the field in Saudi Arabia.

A series of quinazolinone amino acid ester and quinazolinone amino acid hydrazides were prepared under microwave irradiation as well as conventional condition. The microwave irradiation afforded the product in less reaction time, higher yield and purity. The structures of the synthesized compounds were confirmed by IR, NMR, and elemental analysis. The new synthesized compounds were studied for their monoamine oxidase inhibitory activity. They showed more selective inhibitory activity toward MAO-A than MAO-B. Compounds 7, 10, and 15 showed MAO-A inhibition activity (IC50=3.6×10(-9), 2.8×10(-9), 2.1×10(-9) M, respectively) comparable to that of the standard clorgyline (IC50=2.9×10(-9)M). 2-(2-(Benzo[d][1,3]dioxol-5-yl)-4-oxo-1,2-dihydroquinazolin-3(4H)-yl)acetohydrazide 15 showed selective MAO-A inhibition activity (SI=39524) superior to that of the standard clorgyline (SI=33793). The acute toxicity of the synthesized compounds was determined. In addition, computer-assisted simulated docking experiments were performed to rationalize the biological activity., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Synthesis and structure elucidation of new series of novel fused 1,2,4-triazine derivatives 3a-3f, 4a-4i and 6a-6b and their inhibitory activities are presented. Molecular structures of the synthesized compounds were confirmed by (1)H NMR, (13)C NMR, MS spectra and elemental analyses. X-ray crystallographic analysis was performed on 2-acetyl-8-(N,N-diacetylamino)-6-(4-methoxybenzyl)-3-(4-methoxy-phenyl)-7-oxo-2,3-dihydro-7H-[1,2,4]triazolo[4,3-b][1,2,4]triazine 3d and 2-acetyl-8-(N-acetylamino)-6-benzyl-3-(4-chlorophenyl)-3-methyl-7-oxo-2,3-dihydro-7H-[1,2,4]triazolo[4,3-b][1,2,4]triazine 4e to secure their structures. The inhibitory effect of these compounds toward the CPY1A1 activity was screened to determine their potential as promising anticancer drugs. Our data showed that compounds 4e, 5a, 5b and 6b possess the highest inhibitory effects among all tested compounds. Furthermore, analysis of triazolotriazine derivatives docking showed that these compounds bind only at the interface of substrate recognition site 2 (SRS2) and (SRS6) at the outer surface of the protein. Amino-acids ASN214, SER216 and ILE462 participate in the binding of these compounds through H-bonds., (Copyright © 2012 Elsevier Ltd. All rights reserved.)