Discovery of Novel Pyridazine-Tethered Sulfonamides as Carbonic Anhydrase II Inhibitors for the Management of Glaucoma

Tawfik, Haytham O.; Saleh, Mohamed M.; Ammara, Andrea; Khaleel, Eman F.; Badi, Rehab; Khater, Yomna T. T.; Rasheed, Rabab A.; Attia, Ahmed A.; Hefny, Salma M.; Elkaeed, Eslam B.; Nocentini, Alessio; Supuran, Claudiu T.; Eldehna, Wagdy M.; Shaldam, Moataz A.

doi:10.1021/acs.jmedchem.3c02279

Cited by 9 publications

(1 citation statement)

References 52 publications

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“…The core sequences of the human CAs are at least 30% identical, and all of the CA isoforms’ active regions exhibit significant conservation. , Planning isoform-selective CAIs for CA IX with little off-target activity is challenging due to the high conservation of amino acids among different isoforms.…”

Section: Resultsmentioning

confidence: 99%

Discovery and Mechanistic Studies of Dual-Target Hits for Carbonic Anhydrase IX and VEGFR-2 as Potential Agents for Solid Tumors: X-ray, In Vitro, In Vivo, and In Silico Investigations of Coumarin-Based Thiazoles

Hefny,

El-Moselhy,

El-Din

et al. 2024

J. Med. Chem.

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A dual-targeting approach is predicted to yield better cancer therapy outcomes. Consequently, a series of coumarin-based thiazoles (5a−h, 6, and 7a−e) were designed and constructed as potential carbonic anhydrase (CA) and VEGFR-2 suppressors. The inhibitory actions of the target compounds were assessed against CA isoforms IX and VEGFR-2. The assay results showed that coumarin-based thiazoles 5a, 5d, and 5e can effectively inhibit both targets. 5a, 5d, and 5e cytotoxic effects were tested on pancreatic, breast, and prostate cancer cells (PANC1, MCF7, and PC3). Further mechanistic investigation disclosed the ability of 5e to interrupt the PANC1 cell progression in the S stage by triggering the apoptotic cascade, as seen by increased levels of caspases 3, 9, and BAX, alongside the Bcl-2 decline. Moreover, the in vivo efficacy of compound 5e as an antitumor agent was evaluated. Also, molecular docking and dynamics displayed distinctive interactions between 5e and CA IX and VEGFR-2 binding pockets.

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Section: Resultsmentioning

confidence: 99%

Discovery and Mechanistic Studies of Dual-Target Hits for Carbonic Anhydrase IX and VEGFR-2 as Potential Agents for Solid Tumors: X-ray, In Vitro, In Vivo, and In Silico Investigations of Coumarin-Based Thiazoles

Hefny,

El-Moselhy,

El-Din

et al. 2024

J. Med. Chem.

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Tail‐approach based design, synthesis, and molecular modeling of benzenesulfonamides carrying thiadiazole and urea moieties as novel carbonic anhydrase inhibitors

Han,

Gündüz,

Ammara

et al. 2024

Archiv der Pharmazie

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We synthesized herein 16 compounds (SUT1–SUT16) as potential carbonic anhydrase (CA) inhibitors utilizing the tail‐approach design. Based on this strategy, we connected benzenesulfonamide, the zinc‐binding scaffold, to different urea moieties with the 1,3,4‐thiadiazole ring as a linker. We obtained the target compounds by the reaction of 4‐(5‐amino‐1,3,4‐thiadiazol‐2‐yl)benzenesulfonamide with aryl isocyanates. Upon confirmation of their structures, the compounds were screened for their ability to inhibit the tumor‐related human (h) isoforms human carbonic anhydrase (hCA) IX and XII, as well as the physiologically dominant hCA I and II. Most of the molecules demonstrated Ki values ≤ 10 nM with different selectivity profiles. The binding modes of SUT9, SUT10, and SUT5, the most effective inhibitors of hCA II, IX, and XII, respectively, were predicted by molecular docking. SUT16 (4‐{5‐[3‐(naphthalen‐1‐yl)ureido]‐1,3,4‐thiadiazol‐2‐yl}benzenesulfonamide) was found to be the most selective inhibitor of the cancer‐associated isoforms hCA IX and XII over the off‐target isoforms, hCAI and II. The interaction dynamics and stability of SUT16 within hCA IX and XII were investigated by molecular dynamics simulations as well as dynophore analysis. Based on computational data, increased hydrophobic contacts and hydrogen bonds in the tail part of these molecules within hCA IX and XII were found as favorable interactions leading to effective inhibitors of cancer‐related isoforms.

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Explore new quinoxaline pharmacophore tethered sulfonamide fragments as in vitro α‐glucosidase, α‐amylase, and acetylcholinesterase inhibitors with ADMET and molecular modeling simulation

Ragab,

Salem,

Ammar

et al. 2024

Drug Development Research

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A new series of quinoxaline‐sulfonamide derivatives 3–12 were synthesized using fragment‐based drug design by reaction of quinoxaline sulfonyl chloride (QSC) with different amines and hydrazines. The quinoxaline‐sulfonamide derivatives were evaluated for antidiabetic and anti‐Alzheimer's potential against α‐glucosidase, α‐amylase, and acetylcholinesterase enzymes. These derivatives showed good to moderate potency against α‐amylase and α‐glucosidase with inhibitory percentages between 24.34 ± 0.01%–63.09 ± 0.02% and 28.95 ± 0.04%–75.36 ± 0.01%, respectively. Surprisingly, bis‐sulfonamide quinoxaline derivative 4 revealed the most potent activity with inhibitory percentages of 75.36 ± 0.01% and 63.09 ± 0.02% against α‐glucosidase and α‐amylase compared to acarbose (IP = 57.79 ± 0.01% and 67.33 ± 0.01%), respectively. Moreover, the quinoxaline derivative 3 exhibited potency as α‐glucosidase and α‐amylase inhibitory with a minute decline from compound 4 and acarbose with inhibitory percentages of 44.93 ± 0.01% and 38.95 ± 0.01%. Additionally, in vitro acetylcholinesterase inhibitory activity for designed derivatives exhibited weak to moderate activity. Still, sulfonamide‐quinoxaline derivative 3 emerged as the most active member with inhibitory percentage of 41.92 ± 0.02% compared with donepezil (IP = 67.27 ± 0.60%). The DFT calculations, docking simulation, target prediction, and ADMET analysis were performed and discussed in detail.

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Discovery of Novel Pyridazine-Tethered Sulfonamides as Carbonic Anhydrase II Inhibitors for the Management of Glaucoma

Cited by 9 publications

References 52 publications

Discovery and Mechanistic Studies of Dual-Target Hits for Carbonic Anhydrase IX and VEGFR-2 as Potential Agents for Solid Tumors: X-ray, In Vitro, In Vivo, and In Silico Investigations of Coumarin-Based Thiazoles

Discovery and Mechanistic Studies of Dual-Target Hits for Carbonic Anhydrase IX and VEGFR-2 as Potential Agents for Solid Tumors: X-ray, In Vitro, In Vivo, and In Silico Investigations of Coumarin-Based Thiazoles

Tail‐approach based design, synthesis, and molecular modeling of benzenesulfonamides carrying thiadiazole and urea moieties as novel carbonic anhydrase inhibitors

Explore new quinoxaline pharmacophore tethered sulfonamide fragments as in vitro α‐glucosidase, α‐amylase, and acetylcholinesterase inhibitors with ADMET and molecular modeling simulation

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