Mohamed Nabil Abd Al Moaty

Currently, the development of effective and safe antidiabetic drugs remains a major challenge in diabetes management. This study reports the design and synthesis of new quinoline-based hybrids, featuring an oxymethylene-linked 1,2,3-triazole core and integrated 1,2,4-triazole pharmacophores, alongside their chitosan-encapsulated derivatives, as prospective multitarget antidiabetic agents. The synthesized compounds were evaluated for their in vitro inhibitory activity against α-amylase and α-glucosidase, as well as for glucose uptake stimulation and their antioxidant potential through NO and DPPH radical scavenging assays. Notably, CNPs 5* and 6* demonstrated significant α-amylase and α-glucosidase inhibitory potencies, surpassing that of the standard drug acarbose. Compound 6* (IC₅₀ = 0.17 µM) exhibited the most potent α-amylase inhibition compared to acarbose (IC₅₀ = 25.08 µM), alongside demonstrating significant NO radical scavenging activity with a potency ∼1.78-fold greater than ascorbic acid. Furthermore, it stimulated glucose uptake at a level ∼1.65-fold higher than Berberine. CNPs 5* (IC₅₀ = 58.21 µM) was identified as the most potent α-glucosidase inhibitor, surpassing acarbose (IC₅₀ = 68.91 µM). To elucidate the electronic properties and stability of the new hybrids, DFT calculations were performed. Subsequently, molecular docking studies were conducted to corroborate the in vitro findings and explore the binding interactions within the active sites of the target enzymes. Finally, ADME profiles of the new hybrids suggest their promising drug-like properties and support further investigation as potential antidiabetic leads.

Objective: A series of novel derivatives based on a 1,2,4-oxadiazole scaffold were designed, synthesized, and evaluated in vitro for their inhibitory activity against trypsin, aldehyde dehydrogenase 2 (ALDH2), and inducible nitric oxide synthase (iNOS), aiming to identify potential anticancer agents. Methods: The synthesized 1,2,4-oxadiazole derivatives were characterized by NMR, IR spectroscopy, and elemental analysis. Their biological activity was evaluated through in vitro enzyme inhibition assays and supported by molecular docking studies using MOE software. Results and Discussion: The results demonstrated that compounds (Va), (Vb), and (VIIb) exhibited potent trypsin inhibition, exceeding that of the reference compound benzamidine hydrochloride. Additionally, derivatives (IIIa) and (IIIb) also showed notable trypsin inhibitory activity. Compounds (Va) and (VIa) displayed significant ALDH2 inhibition, comparable to that of tetraethylthiuram disulfide. Furthermore, derivatives (VIa), (VIb), and (VIIIb) effectively inhibited iNOS. The pronounced inhibitory activities of the most potent compounds (Va, VIa, and VIIb) may be attributed to strong interactions within the active sites of trypsin and ALDH2, as supported by molecular docking studies. Compound (Va) also exhibited favorable physicochemical properties, suggesting its potential as a promising lead compound for further drug development. Conclusions: 1,2,4-Oxadiazole derivative (Va) appears to be a promising anticancer lead compound for further investigation and development.

The 3,5‐diaryl‐1,2,4‐oxadiazole scaffolds 2 and 3 were synthesized and used as ligands to obtain three novel Ag(I) complexes 4–6 . The structure of the Ag(I) complexes 4–6 has been confirmed by single crystal X‐ray diffraction. Complex 4 has the dinuclear formula [Ag(2)(NO ₃ )] ₂ . 5 and 6 are monomeric complexes having the formula [Ag(3) ₂ (NO ₃ )] and [Ag(3) ₂ ]ClO ₄ , respectively. In vitro, trypsin, ALDH2, and iNOS inhibition activities were assessed for the free ligands and their Ag(I) complexes. Interestingly, Ag(I) complexes 4–6 revealed more prominent trypsin inhibitory activity than the ligands 2 and 3 . The oxadiazole derivative 3 and its Ag(I) complex ( 6 ) showed significant ALDH2 inhibition (45% and 55%, respectively). Complex 6 (IC ₅₀ = 35.61 μM) surpassed its 1,2,4‐oxadiazole ligand 3 (IC ₅₀ = 88 μM) and evidenced the most prominent ALDH2 inhibitory activity. The oxadiazole derivative 3 and its corresponding Ag(I) complexes 5 and 6 showed significant iNOS inhibition (77.77%, 84.12%, and 84.15%, respectively). With IC ₅₀ values of 18.13, 18.15, and 13.96 μM, respectively, complex 6 is the most potent against iNOS, surpassing the reference standard.

Combinations of apoptotic inducers are common clinical practice in breast cancer. However, their efficacy is limited by the heterogeneous pharmacokinetic profiles. An advantageous alternative is merging their molecular entities in hybrid multitargeted scaffolds exhibiting synergistic activities and uniform distribution. Herein, we report apoptotic inducers simultaneously targeting DNA and CDK-2 (cyclin-dependent kinase-2) inspired by studies revealing that CDK-2 inhibition sensitizes breast cancer to DNA-damaging agents. Accordingly, rationally substituted pyrimidines and triazolopyrimidines were synthesized and assayed by MTT against MCF-7, MDA-MB231, and Wi-38 cells compared to doxorubicin. The N-(4-amino-2-((2-hydrazinyl-2-oxoethyl)thio)-6-oxo-1,6-dihydropyrimidin-5-yl)acetamide 5 and its p-nitrophenylhydrazone 8 were the study hits against MCF-7 (IC₅₀ = 0.050 and 0.146 μM) and MDA-MB231 (IC₅₀ = 0.826 and 0.583 μM), induced DNA damage at 10.64 and 30.03 nM, and inhibited CDK-2 (IC₅₀ = 0.172 and 0.189 μM). 5 induced MCF-7 apoptosis by 46.75% and disrupted cell cycle during S phase. Docking and MD simulations postulated their stable key interactions.

Breast cancer continues to be the most frequent cancer worldwide. In practice, successful clinical outcomes were achieved via targeting DNA. Along with the advances in introducing new DNA‐targeting agents, the “sugar approach” design was employed herein to develop new intercalators bearing pharmacophoric motifs tethered to carbohydrate appendages. Accordingly, new benzimidazole acyclic C‐nucleosides were rationally designed, synthesized and assayed via MTT (3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5 diphenyl tetrazolium bromide) assay to evaluate their cytotoxicity against MCF‐7 and MDA‐MB‐231 breast cancer cells compared to normal fibroblasts (Wi‐38), compared to doxorubicin. (1S,2R,3S,4R)‐2‐(1,2,3,4,5‐Pentahydroxy)pentyl‐1H‐5,6‐dichlorobenzimidazole 7 and (1S,2R,3S,4R)‐2‐(1,2,3,4,5‐pentahydroxy)pentyl‐1H‐naphthimidazole 13 were the most potent and selective derivatives against MCF‐7 (half‐maximal inhibitory concentration [IC₅₀] = 0.060 and 0.080 µM, selectivity index [SI] = 9.68 and 8.27, respectively) and MDA‐MB‐231 cells (IC₅₀ = 0.299 and 0.166 µM, SI = 1.94 and 3.98, respectively). Thus, they were identified as the study hits for mechanistic studies. Both derivatives induced DNA damage at 0.24 and 0.29 μM, respectively. The DNA damage kinetics were studied compared to doxorubicin, where they both induced faster damage than doxorubicin. This indicated that 7 and 13 showed a more potent DNA‐damaging effect than doxorubicin. Docking simulations within the DNA double strands highlighted the role of both the heterocyclic core and the sugar side chain in exhibiting key H‐bond interactions with DNA bases.

Biofilms are matrix-enclosed communities of bacteria that are highly resistant to antibiotics. Adding nanomaterials with antibacterial activity to the implant surfaces may be a great solution against biofilm formation. Due to its potent and widespread antibacterial effect, silver nanoparticles were considered the most potent agent with different biological activities. In the present investigation, silver nanoparticles (AgNPs) were newly synthesized as antibiofilm agents using sugarcane process byproduct (molasses) and named Mo-capped AgNPs. The synthesized nanoparticles showed promising antimicrobial activity against S. aureus ATCC 6538 and C. albicans DAY185. Statistically designed optimization through response surface methodology was evaluated for maximum activity and better physical characteristics, namely the nanoparticles’ size and polydispersity index (PDI), and it was revealed that molasses concentration was the main effective factor. Minimal biofilm eradication concentration (MBEC) of Mo-capped AgNPs against S. aureus ATCC 6538 and C. albicans DAY185 was 16 and 32 µg/mL, respectively. Scanning electron microscope study of Mo-capped AgNP-treated biofilm revealed that AgNPs penetrated the preformed biofilm and eradicated the microbial cells. The optimally synthesized Mo-capped AgNPs were spherically shaped, and the average size diameter ranged between 29 and 88 nm with high proportions of Ag⁺ element (78.0%) recorded. Fourier-transform infrared spectroscopy (FTIR) analysis indicated the importance of molasses ingredients in capping and stabilizing the produced silver nanoparticles.

Based on the "canonical" view of reactive oxygen species' (ROS) contribution to carcinogenesis, ROS induce oxidative stress and promote various tumor progression events. However, tumor cells also need to defend themselves against oxidative damage. This "heresy" was supported by several recent studies underlining the role of cellular antioxidant capacity in promoting metastasis and resistance to chemotherapy. Accordingly, harnessing the ROS-induced oxidative stress via selective suppression of the cancer antioxidant defense machinery has been launched as an innovative anticancer strategy. Within this approach, pharmacological inhibition of superoxide dismutases (SODs), the first-line defense antioxidant enzymes for cancer cells, selectively kills tumor cells and circumvents their acquired resistance. Various SOD inhibitors have been introduced, of which some were tolerated in clinical trials. However, the hit SOD inhibitors belong to diverse chemical classes and lack comprehensive structure-activity relationships (SAR). Herein, we probe the potential of newly synthesized benzylidene thiazolidinedione derivatives to inhibit SOD in colorectal cancer with special emphasis on their effects on correlated antioxidant enzymes aldehyde dehydrogenase 1 (ALDH1) and glutathione peroxidase (GPx). This may possibly bring a new dawn for utilizing thiazolidinediones (TZDs) in cancer therapy through SOD inhibition mechanisms. The preliminary 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that all of the evaluated TZDs exhibited excellent safety profiles on normal human cells, recording an EC100 of up to 47.5-folds higher than that of doxorubicin. Compounds 3c, 6a, and 6e (IC50 = 4.4-4.7 μM) were superior to doxorubicin and other derivatives against Caco-2 colorectal cancer cells within their safe doses. The hit anticancer agents inhibited SOD (IC50 = 97.2-228.8 μM). Then, they were selected for further in-depth evaluation on the cellular level. The anticancer IC50 doses of 3c, 6a, and 6e diminished the antioxidant activities of SOD (by 29.7, 70.1, and 33.3%, respectively), ALDH1A (by 85.92, 95.84, and 86.48%, respectively), and GPX (by 50.17, 87.03, and 53.28%, respectively) in the treated Caco-2 cells, elevating the Caco-2 cellular content of ROS by 21.42, 7.863, and 8.986-folds, respectively. Docking simulations were conducted to display their possible binding modes and essential structural features. Also, their physicochemical parameters and pharmacokinetic profiles formulating drug-likeness were computed.

The role of metalloenzymes in tumor progression had broadened their application in cancer therapy. Of these, MMPs and CAs are validated druggable targets that share some pivotal signaling pathways. The majority of MMPs or CAs inhibitors are designed as single-target agents. Despite their transient efficacy, these agents are often susceptible to resistance. This set the stage to introduce dual inhibitors of correlated MMPs and CAs. The next step is expected to target the common vital signaling nodes as well. In this regard, VEGFR-2 is central to various tumorigenesis events involving both families, especially MMP-2 and CA II. Herein, we report simultaneous inhibition of MMP-2, CA II, and VEGFR-2 via rationally designed hybrid 1,2,4-triazolo[4,3-a]pyrimidinone acyclo C-nucleosides. The promising derivatives were nanomolar inhibitors of VEGFR-2 (8; IC₅₀ = 5.89 nM, 9; IC₅₀ = 10.52 nM) and MMP-2 (8; IC₅₀ = 17.44 nM, 9; IC₅₀ = 30.93 nM) and submicromolar inhibitors of CA II (8; IC₅₀ = 0.21 µM, 9; IC₅₀ = 0.36 µM). Docking studies predicted their binding modes into the enzyme active sites and the structural determinants of activity regarding substitution and regioselectivity. MTT assay demonstrated that both compounds were 12 folds safer than doxorubicin with superior anticancer activities against three human cancers recording single-digit nanomolar IC₅₀, thus echoing their enzymatic activities. Up to our knowledge, this study introduces the first in class triazolopyrimidinone acyclo C-nucleosides VEGFR-2/MMP-2/CA II inhibitors that deserve further investigation.

Matrix metalloproteinases (MMPs) are key signaling modulators in the tumor microenvironment. Among MMPs, MMP-2 and MMP-9 are receiving renewed interest as validated druggable targets for halting different tumor progression events. Over the last decades, a diverse range of MMP-2/9 inhibitors has been identified starting from the early hydroxamic acid-based peptidomimetics to the next generation non-hydroxamates. Herein, focused 1,2,4-triazole-1,2,3-triazole molecular hybrids with varying lengths and decorations, mimicking the thematic features of non-hydroxamate inhibitors, were designed and synthesized using efficient protocols and were alkylated with pharmacophoric amines to develop new Mannich bases. After full spectroscopic characterization the newly synthesized triazoles tethering Mannich bases were subjected to safety assessment via MTT assay against normal human fibroblasts, then evaluated for their potential anticancer activities against colon (Caco-2) and breast (MDA-MB 231) cancers. The relatively lengthy bis-Mannich bases 15 and 16 were safer and more potent than 5-fluorouracil with sub-micromolar IC₅₀ and promising selectivity to the screened cancer cell lines rather than normal cells. Both compounds upregulated p53 (2–5.6-fold) and suppressed cyclin D expression (0.8–0.2-fold) in the studied cancers, and thus, induced apoptosis. 15 was superior to 16 in terms of cytotoxic activities, p53 induction, and cyclin D suppression. Mechanistically, both were efficient MMP-2/9 inhibitors with comparable potencies to the reference prototype hydroxamate-based MMP inhibitor NNGH at their anticancer IC₅₀ concentrations. 15 (IC₅₀ = 0.143 µM) was 4-fold more potent than NNGH against MMP-9 with promising selectivity (3.27-fold) over MMP-2, whereas 16 was comparable to NNGH. Concerning MMP-2, 16 (IC₅₀ = 0.376 µM) was 1.2-fold more active than 15. Docking simulations predicted their possible binding modes and highlighted the possible structural determinants of MMP-2/9 inhibitory activities. Computational prediction of their physicochemical properties, ADMET, and drug-likeness metrics revealed acceptable drug-like criteria.