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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.

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.

A series of 6-methylpyrimidin-4(3H)-one and oxo-1,2,4-triazolo[4,3-a]pyrimidine derivatives (1-18) was designed to meet the urgent need for novel antibacterial and antioxidant agents. The in vitro antibacterial activity revealed that most of the compounds exhibited a good inhibitory effect on Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) bacteria with MIC values in the range of 55–200 µg/mL for E. coli and 125–700 µg/mL for S. aureus. (E)-2-(2-(4-methoxybenzylidene)hydrazinyl)-6-methylpyrimidin-4(3H)-one (8) was the most active compound (MIC = 55 and 125 µg/mL against E. coli and S. aureus, respectively). All compounds exhibited antioxidant activity ranged from weak to moderate and high. The obtained findings revealed that compounds 3, 5, 6, 9, 16, and 18 have superiority among all compounds, demonstrating the highest capacity to deplete DPPH (1,1-diphenyl-2-picrylhydrazyl), compared to α-tocopherol, as a standard antioxidant agent. Surprisingly, compound 3 (2-hydrazinyl-6-methylpyrimidin-4(3H)-one) showed significantly higher antioxidant activity (EC50 = 2.12 µg/mL) than α-tocopherol (EC50 = 9.16 µg/mL). Molecular docking, drug-likeness data, physicochemical properties, and ADMET parameters of the compounds were in silico computed. The derivatives presented good properties for Lipinski’s parameters, poor solubility in the aqueous medium (Log S of -1.27 to -5.45), and PSA ≤140, indicating good permeability in biological membranes and gastrointestinal absorption. Molecular docking to the active sites of penicillin-binding protein and NADPH oxidase revealed that most compounds displayed minimal binding energy and have a good affinity toward the active pocket.

In this work, the synthesis of novel 1,2,4-triazole thioglycoside heterocycles 4, 5, and 8 were achieved by the reaction of 1,2,3,4,6-penta-O-acetyl-β- d -glucopyranose (2) and galactopyranose (3) with 4-((4-arylidene)amino)-5-methyl-1,2,4-triazole-3-thiol derivatives 1 and 6 in the presence of boron trifluoride etherate (BF3·Et2O) as a promoter under nitrogen in CH2Cl2. Exclusive β-stereoselectivity of the formed glycosidic bond was confirmed by X-ray analysis of 4 as well as its spectral data. Different stereoselectivities were observed when the acceptor 9, having an ortho phenolic OH group, was coupled with the donors 2 or 3, under the same reaction conditions. Similarly, treatment of a mixture of 1-O-acetyl-2,3,5-tri-O-benzoyl-β- d -ribofuranose (16) and the thiol acceptors 1 and 15 afforded the β-thioribofuranosides 17 and 18, respectively. The β-stereoselectivity of the reaction was confirmed by 1H, 13C, 1H 1H 2D, and 1H 13C 2D NMR spectral analysis.

Reaction of 4-amino-3-methyl-1,2,4-triazole-5-thione with some substituted benzaldehydes in presence of catalytic amount of hydrochloric acid afforded the respective Schiff's bases 3a-e. Computational studies using DFT incorporating the B3LYP/6-311G(d,p) level of theory is used to predict the stability of the possible tautomers. Molecular modeling, natural charge calculations, NMR, Frontier molecular orbitals and electronic spectra were investigated. Analysis of the thermodynamic parameters of the thione-thiol tautomeric reactions of these derivatives was used to predict the tautomers stability. The thione tautomer is the most favored form in gas phase and in solution whatever the nature of solvent used. The electronic spectra were assigned based on the TD-DFT calculations. The GIAO NMR chemical shifts correlated well with the experimental data.

Recently, interest in matrix metalloproteinases (MMPs) -10 and -13 has been revitalized with the growing knowledge on their relevance within the MMPs network and significance of their inhibition for treatment of various diseases like arthritis, cancer, atherosclerosis and Alzheimer. Within this approach, dual MMP-10/13 inhibition was disclosed as new approach for targeted polypharmacology. While several efficient MMP-13 inhibitors are known, very few potent and selective MMP-10 inhibitors were reported. This study describes the design, synthesis and optimization of novel MMP-10/13 inhibitors with enhanced MMP-10 potency and selectivity towards polypharmacology. Starting with a lead fused pyrimidine-based MMP-13 inhibitor with weak MMP-10 inhibition, a structure-based design of pyrimidine and fused pyrimidine scaffolds was rationalized to enhance activity against MMP-10 in parallel with MMP-13. Firstly, a series of 6-methyl pyrimidin-4-one hydrazones 6–10 was synthesized via conventional and ultrasonic-assisted methods, then evaluated for MMP-10/13 inhibition. The most active derivative 9 exhibited acceptable dual potency with 7-fold selectivity for MMP-10 (IC50 = 53 nM) over MMP-13. Such hydrazones were then cyclized to the corresponding isomeric 1,2,4-triazolo[4,3-a]pyrimidines 12–19. Their MMP-10/13 inhibition assay revealed, in most cases, superior dual activities with general MMP-10 selectivity compared to the corresponding precursors 6–10. In addition, a clear structure activity relationship trend was deduced within the identified regioisomers, where the 5-oxo-1,2,4-triazolo[4,3-a]pyrimidine derivatives 15 and 16 were far more active against MMP-10/13 than their regioisomers 12 and 13. Remarkably, the p-bromophenyl derivative 16 exhibited the highest MMP-10 inhibition (IC50 = 24 nM), whereas the p-methoxy derivative 18 was the most potent MMP-13 inhibitor (IC50 = 294 nM). Moreover, 16 exhibited 19-fold selectivity for MMP-10 over MMP-13, 10-fold over MMP-9, and 29-fold over MMP-7. Docking studies were performed to provide reasonable explanation for structure-activity relationships and isoform selectivity. 16 and 18 were then evaluated for their anticancer activities against three human cancers to assess their therapeutic potential at cellular level via MTT assay. Both compounds exhibited superior anticancer activities compared to quercetin. Their in silico ligand efficiency metrics, physicochemical properties and ADME parameters were drug-like. Guided by such findings that point to 16 as the most promising compound in this study, further structure optimization was carried out via photoirradiation-mediated Dimroth rearrangement of the inactive triazolopyrimidine 13 to its potent regioisomer 16.