The research and design of new inhibitors for the treatment of diseases such as Alzheimer's disease and glaucoma through inhibition of cholinesterases (ChEs; acetylcholinesterase, AChE and butyrylcholinesterase, BChE) and carbonic anhydrase enzymes are among the important targets. Here, a series of novel sulfonamide‐bearing pyrazolone derivatives (1a–f and 2a–f) were successfully synthesized and characterized by using spectroscopic and analytical methods. The inhibitory activities of these newly synthesized compounds were evaluated both in vitro and in silico for their effect on carbonic anhydrases (hCA I and hCA II isoenzymes) and ChEs. The in vitro studies showed that these novel compounds demonstrated potential inhibitory activity, with K_I values covering the following ranges: 18.03 ± 2.86–75.54 ± 4.91 nM for hCA I, 24.84 ± 1.57–85.42 ± 6.60 nM for hCA II, 7.45 ± 0.98–16.04 ± 1.60 nM for AChE, and 34.78 ± 5.88–135.70 ± 17.39 nM for BChE. Additionally, many of these compounds showed promising inhibitory activity, and some showed higher potency than reference compounds. While the in silico studies have also identified the potential binding positions of these compounds, using the crystal structures of hCA I, II, AChE and BChE receptors. The varying affinities demonstrated by these designed compounds for ChEs and hCA isoenzymes show that these compounds could hold promise as potential alternative agents for selectively inhibiting ChEs and hCAs in the treatment of diseases such as Alzheimer's disease and glaucoma.

Background/Objectives: Pyrazole carboxamides are widely used as adaptable medicinal-chemistry scaffolds and have been explored as cholinesterase (ChE) inhibitor chemotypes. In this work, we prepared a new series of 4-arylazo-3,5-diamino-N-tosyl-1H-pyrazole-1-carboxamides 5(a–m) and evaluated their inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), supported by structure-based computational analyses. Methods: Thirteen derivatives 5(a–m) were synthesized, fully characterized with analytical techniques (FT-IR, H NMR, and C NMR), and tested in vitro against AChE and BChE, with tacrine (THA) used as the reference inhibitor. Docking calculations were used to examine plausible binding modes. The top-ranked complexes (7XN1–5e and 4BDS–5i) were further examined by 100 ns explicit-solvent molecular dynamics (MD) simulations in Cresset Flare, followed by RMSD/RMSF analysis and contact-persistence profiling. Predicted ADME/Tox. properties were also assessed to identify potential developability issues. Results: The series showed strong ChE inhibition, and several compounds were more potent than THA. Compound 5e (4-nitro) was the most active AChE inhibitor (K_I = 20.86 ± 1.61 nM) compared with THA (K_I = 164.40 ± 20.84 nM). For BChE, the K_I values ranged from 31.21 to 87.07 nM and exceeded the reference compound’s activity. MD trajectories supported stable binding in both systems (10–100 ns mean backbone RMSD: 2.21 ± 0.17 Å for 7XN1–5e; 1.89 ± 0.11 Å for 4BDS–5i). Most fluctuations were confined to flexible regions, while key contacts remained in place, consistent with the docking models. ADME/Tox. predictions suggested moderate lipophilicity but generally low aqueous solubility; all compounds were predicted as non-BBB permeant, and selected liabilities were flagged (e.g., carcinogenicity for 5e/5g/5h/5i; nephrotoxicity for 5f/5g). Conclusions: The 4-arylazo-3,5-diamino-N-tosyl-1H-pyrazole-1-carboxamide scaffold delivers low-nanomolar ChE inhibition, with docking and MD supporting stable binding modes. Future optimization should prioritize solubility improvement and mitigation of predicted toxicities and metabolic liabilities, especially given the predicted lack of BBB permeability for CNS-directed applications.

A series of twenty 1,3,5-triazine-substituted ureido benzenesulfonamides 2 (a-e) and 3 (a-o) were re-synthesized and assayed for antioxidant properties by using several different methods including 1,1-diphenyl-2-picryl hydrazyl (DPPH) free radical scavenging assay, 2,2′-azino-bis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) cation radical decolarization assay, metal chelating and cupric reducing antioxidant capacity (CUPRAC) methods. The inhibitory effects of compounds on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes have been also demonstrated. All compounds showed a greater antioxidant capacity against ABTS assay by having a more potent activity than the standards BHT, BHA and α-TOC. In general, all compounds were non susceptible to against AChE enzyme. On the other hand, several lead compounds were obtained from the current series against BChE enzyme. More specifically, compound 3m showed great inhibition profile against BChE with % inhibition value of 93.77, which is better than the standard drug galantamine (% inhibition value of 87.86).

Multidrug resistance (MDR) causes difficulties in the treatment of infections and cancer. Research and development studies have become increasingly important for the strategy of preventing MDR. There is a need for new multitarget drug research and advancement to reduce the development of drug resistance in drug‐drug interactions and reduce cost and toxic effects. This study aimed to determine the effects of multi‐target triazene compounds on antibacterial, antifungal, antiviral, cytotoxic, and larvicidal activities were investigated in vitro. A series of 12 novel of 1,3‐diaryltriazene‐substituted sulfadiazine (SDZ) derivatives were synthesized, and the obtained pure products characterized in detail by spectroscopic and analytic methods (FT‐IR, ¹H‐NMR, ¹³C‐NMR, and melting points). The antibacterial and antifungal activities of these derivatives (AH1‐12) were determined by broth microdilution method. All derivatives have been evaluated in cell‐based assays for cytotoxic and antiviral activities against Modified Vaccinia Virus Ankara. The larvicidal efficacy of these chemical compounds was also investigated by using Lucilia sericata (L. sericata) larvae. Twelve 1,3‐diaryltriazene‐substituted SDZ derivatives (AH1‐12) were designed and developed as potent multitargeted compounds. Among them, the AH1 derivative showed the most antibacterial and antifungal activity. Besides, synthesized derivatives AH2, AH3, AH5, and AH7 showed higher antiviral activity than SDZ. All synthesized derivatives showed higher cytotoxic activity than SDZ. Also, they showed larvicidal activity at 72 h of the experiment. As a result, these compounds might be great leads for the development of next‐generation multitargeted agents.

Herein, a series of twelve bis-hydrazone substituted isovanilline derivatives 3(a-l), were freshly re-synthesized by the reaction of bis-aldehydes with substituted hydrazide derivatives since these compounds previously showed potent aldose reductase inhibition properties. The obtained compounds were tested for their potential antibacterial and antioxidant activities. In the present study, four different bacterial strains were used, including Gram-positive (Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 29212) and Gram-negative (Pseudomonas aeruginosa ATCC 10231, Escherichia coli ATCC 25912). On the other hand, the antioxidant capacities of freshly re-synthesized bis-hydrazone substituted isovanilline derivatives were determined by using several antioxidant methods, including DPPH free radical scanvenging, TEAC cupric reducing (CUPRAC) and metal chelating activity methods. Several lead molecules were discovered as a potential bacterial inhibitors against S. aureus and E. coli bacterial strains. More specifically, compounds 3g (R=-H) and 3j (R= -4Cl) showed great inhibition properties against E. coli bacterial strains by having MIC values of 1.56 and 6.25 µg/mL, respectively. Moreover, none of the compounds showed potent antioxidant activity against tested methods with respect to compared standards.