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.

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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.

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.

Reaction of dimedone with arylamines afforded the respective enaminones. Some N-acetyl derivatives were prepared. The reaction of enaminones with hydroxylamine was found to be dependent on the nature of the arylamine moiety and the molar ratio of hydroxylamine to give the mono-, di- or tri-oximes. Cyclization of the trioxime by acetic anhydride gave dihydrobenzo[c][1,2,5]oxadiazol-4(5H)-one-5-O-acetyloxime. Coupling of the synthesized enaminones with benzene diazonium chloride gave 2,4-bis-phenylhydrazones or a mixture of 2-mono hydrazones and bis-hydrazones depending on the nature of the arylamine moiety. Trans-amination of the arylamine of the bis hydrazones with hydroxylamine gave the same1,3-bis oxime derivative. The structures of the synthesized compounds were confirmed by IR, 1HNMR, 13C NMR spectra. The antimicrobial activity of some selected products showed promising results.