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The traditional theory of "one drug, one target, one illness" has come under scrutiny owing to the multifactorial nature of Alzheimer's disease (AD) and the failure of most of its medications, therefore multi-target directed ligands (MTDLs) are prospective therapeutics for AD. In the present study, we synthesized novel series of coumarin derivatives and assessed their inhibitory actions against hAChE, hBuChE, GSK-3β, tau protein and Aβ aggregation. Compounds 6c and 6h stood out among the others with their multifunctional profile. With IC 50 values of 28.88 and 26.03 nM, respectively, compounds 6c and 6h showed outstanding activity as hAChE inhibitors and demonstrated good inhibitory activity against hBuChE with IC 50 values of 103.90 and 90.09 nM along with appropriate action against GSK-3β in nanomolar range. Also, both compounds 6c and 6h were found to outperform the reported anti-AD donepezil as tau protein aggregation and amyloid aggregation (Aβ) inhibitors as well as low cytotoxicity on healthy neuroblastoma SHSY5Y and hepatic THLE2 cells. Kinetic analysis and docking studies indicated hAChE dual site (mixed) inhibitory effect of compound 6h. Both compounds 6c and 6h complied with Lipinski's rule of five and were virtually able to cross the BBB. All the data suggested that compounds 6c and 6h have potential as a multifunctional therapy for AD., 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.)

Sulfonamides have gained prominence as versatile agents in cancer therapy, effectively targeting a spectrum of cancer-associated enzymes. This review provides an extensive exploration of their multifaceted roles in cancer biology. Sulfonamides exhibit adaptability by acting as tyrosine kinase inhibitors, disrupting pivotal signaling pathways in cancer progression. Moreover, they disrupt pH regulation mechanisms in cancer cells as carbonic anhydrase inhibitors, inhibiting growth, and survival. Sulfonamides also serve as aromatase inhibitors, interfering with estrogen synthesis in hormone-driven cancers. Inhibition of matrix metalloproteinases presents an opportunity to impede cancer cell invasion and metastasis. Additionally, their emerging role as histone deacetylase inhibitors offers promising prospects in epigenetic-based cancer therapies. These diverse roles underscore sulfonamides as invaluable tools for innovative anti-cancer treatments, warranting further exploration for enhanced clinical applications and patient outcomes., 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.)

Various pyridopyridazinone derivatives were designed as Poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors. The pyridopyridazinone scaffold was used as an isostere of the phthalazine nucleus of the lead compound Olaparib in addition to some modifications in the tail part of the molecule. Preliminary biological evaluation indicated that most compounds possessed inhibitory potencies comparable to Olaparib in nanomolar level. The best PARP-1 inhibitory activity was observed for compound 8a with (IC 50  = 36 nM) compared to Olaparib as a reference drug (IC 50  = 34 nM). Molecular modeling simulation revealed that, the designed compounds docked well into PARP-1 active site and their complexes are stabilized by three key hydrogen bond interactions with both Gly863 and Ser904 as well as other favorable π-π and hydrogen-π stacking interactions with Tyr907 and Tyr896, respectively. Computational ADME study predicted that the target compounds 8a and 8e have proper pharmacokinetic and drug-likeness properties. These outcomes afford a new structural framework for the design of novel inhibitors for PARP-1., (Copyright © 2019 Elsevier Inc. All rights reserved.)