Novel 3-(6-methylpyridin-2-yl)coumarin-based chalcones as selective inhibitors of cancer-related carbonic anhydrases IX and XII endowed with anti-proliferative activity

Tawfik, Haytham O.; Shaldam, Moataz A.; Nocentini, Alessio; Salem, Rofaida; Almahli, Hadia; Al-Rashood, Sara T.; Supuran, Claudiu T.; Eldehna, Wagdy M.

doi:10.1080/14756366.2022.2056734

Cited by 16 publications

(12 citation statements)

References 41 publications

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“…All herein developed benzothiazole-derived sulphonamides 8a-c , 10 , 12 , 16a-b and the carboxylic acids 14a-c were explored for their potential antitumor activities at the National Cancer Institute (NCI-USA) within the Developmental Therapeutic Program, utilising the US-NCI protocol and the sulforhodamine B (SRB) colorimetric assay for cell growth and viability evaluation 32 , 37 , 42 , 43 .…”

Section: Resultsmentioning

confidence: 99%

Design and synthesis of benzothiazole-based SLC-0111 analogues as new inhibitors for the cancer-associated carbonic anhydrase isoforms IX and XII

Al‐Warhi

Elbadawi

Bonardi

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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In this work, different series of benzothiazole-based sulphonamides 8a-c, 10, 12, 16a-b and carboxylic acids 14a-c were developed as novel SLC-0111 analogues with the goal of generating potent carbonic anhydrase (CA) inhibitors. The adopted strategy involved replacing the 4-fluorophenyl tail in SLC-0111 with a benzothiazole motif that attached to the ureido linker to produce compounds 8c and its regioisomers 8a-b . In addition, the ureido spacer was elongated by methylene or ethylene groups to afford the counterparts 10 and 12 . In turn, the primary sulfamoyl zinc binding group (ZBG) was either substituted or replaced by carboxylic acid functionality in order to provide the secondary sulphonamide-based SLC-0111 analogues 16a-b , and the carboxylic acid derivatives 14a-c , respectively. All compounds ( 8a-c, 10, 12, 14a-c and 16a-b ) were tested for their ability to inhibit CA isoforms CA I, II, IX and XII. Additionally, the in vitro anticancer properties of the developed CAIs were evaluated.

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Section: Resultsmentioning

confidence: 99%

Design and synthesis of benzothiazole-based SLC-0111 analogues as new inhibitors for the cancer-associated carbonic anhydrase isoforms IX and XII

Al‐Warhi

Elbadawi

Bonardi

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…[ 7,8 ] Lately, a group of researchers have designed and synthesized coumarin‐pyridine scaffolds against the target human carbonic anhydrases ( h CA) IX and XII, and have screened with different concentration ranges against the isoforms h CA I & II for a better understanding of the specificity of coumarin toward the target‐the overexpressed isoforms h CA IX & XII in the cancer cell. [ 9 ] With all the above findings the current efforts could parallelly assist the drug development against the cancer target h CA along with the structure–activity relationship for the small molecule conjugation chemistry.…”

Section: Introductionmentioning

confidence: 98%

Coumaryl‐sulfonamide moiety: Unraveling their synthetic strategy and specificity toward hCA IX/XII, facilitating anticancer drug development

Mahapatra

Mekap

Mal

et al. 2023

Archiv der Pharmazie

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Currently, cancer is the most grieving threat to society. The cancer-related death rate has had an ascending trend, despite the implementation of numerous treatment strategies or the discovery of an array of potent molecules against several pathways of cancer growth. The need of the hour is to prevent the multidrug resistance toll, and the current efforts have been bestowed upon a versatile small molecule scaffold, coumarin (benz[α]pyrone), a natural compound possessing interesting affinity toward the cancer target human carbonic anhydrase (hCA), focusing on hCA I, II, IX, and XII. Along with coumarin, the age-old known antibacterial drug sulfonamide, when conjugated at positions 3, 7, and 8 of coumarin either with a linker group or as a single entity, has been reported to enhance the affinity of coumarin toward the overexpressed enzymes in tumor cell lines. The sulfonamides have been listed as obsolete drugs due to the severe side effects caused by them; however, their affinity toward the hCA-zinc-binding core has attracted the attention of researchers. Hence, in the process of drug development, coumarin and sulfonamides have remained the choice of last resort. To unveil the synthetic strategy of coumarin-sulfonamide conjugation, their rationale for inhibiting cancer cells/enzymes, and their affinity toward various types of carcinoma have been the sole goal of the researchers. This review specifically focuses on the mechanism of action and the structure-activity relationship through synthetic strategies and the binding affinity of coumarylsulfonamide conjugates with the anticancer targets possessing the highest enzyme affinity, since 2008.

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“…3,4 One of the ubiquitous metalloenzymes is CAs, which are responsible for the hydration reaction of CO 2 . 5 A total of 16 isoforms were discovered in humans belonging to the α-class. These isoforms respond differently to various modulators and have different tissues and subcellular localization.…”

Section: Introductionmentioning

confidence: 99%

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

Tawfik,

Saleh,

Ammara

et al. 2024

J. Med. Chem.

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As a progressive neuropathic condition, glaucoma can cause lifelong blindness if left untreated. Novel phenylpyridazine-tethered sulfonamides were designed as selective inhibitors for carbonic anhydrase (CA) isoform II to find effective therapeutic agents for glaucoma. Subsequently, the target inhibitors were synthesized and assessed for their inhibitory action against cytosolic CA I and II. Interestingly, the synthesized molecules poorly inhibited CA I while exhibiting low subnanomolar potency against CA II. Compound 7c disclosed the most potent activity (IC 50 = 0.63 nM) with high selectivity against CA II (605-fold than acetazolamide selectivity). Moreover, compound 7c also showed significant in vivo IOP-reducing properties in the in vivo model of glaucoma. Furthermore, the binding of compound 7c to CA II was assessed at the molecular level, exploiting the molecular docking approach.

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Novel 3-(6-methylpyridin-2-yl)coumarin-based chalcones as selective inhibitors of cancer-related carbonic anhydrases IX and XII endowed with anti-proliferative activity

Cited by 16 publications

References 41 publications

Design and synthesis of benzothiazole-based SLC-0111 analogues as new inhibitors for the cancer-associated carbonic anhydrase isoforms IX and XII

Design and synthesis of benzothiazole-based SLC-0111 analogues as new inhibitors for the cancer-associated carbonic anhydrase isoforms IX and XII

Coumaryl‐sulfonamide moiety: Unraveling their synthetic strategy and specificity toward hCA IX/XII, facilitating anticancer drug development

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

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