Synthesis and biological evaluation of new 3-substituted coumarin derivatives as selective inhibitors of human carbonic anhydrase IX and XII

Ghouse, Shaik Mahammad; Bahatam, Kavyaraj; Angeli, Andrea; Pawar, Gaurav; Chinchilli, Krishna Kartheek; Yaddanapudi, Venkata Madhavi; Arifuddin, Mohammed; Supuran, Claudiu T.; Nanduri, Srinivas

doi:10.1080/14756366.2023.2185760

Cited by 9 publications

(8 citation statements)

References 36 publications

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“…Molecular docking and dynamic simulation protocols were adopted from our previous work. [ 28 ] The crystal structure of hCA IX (PDB: 5DVX) [ 36 ] and hCA XII (PDB 1JD0) [ 37 ] were prepared using the Protein Preparation Wizard [ 38 ] and minimized using the OPLS3e force field. The 3D ligand structures were prepared using Ligprep [ 39 ] at pH 7.4 ± 0.5.…”

Section: Methodsmentioning

confidence: 99%

“…[11,15,20,31] The hydrolyzed cinnamate derivative is reported to coordinate with Zn 2+ through COO − . [24] The hydrolyzed structures of the newly synthesized derivatives were drawn, and protocols adopted from the literature [28,30,32] were used to perform molecular docking and dynamic simulations.…”

Section: In Silico Studiesmentioning

confidence: 99%

“…[27] In our previous work, we explored the coumarin linked with various active moieties like sulfonamides and oxime ethers through piperazine, of which compounds VIII and IX showed good inhibition against hCA IX and hCA XII with K i of 4.1 and 9.4 µM, respectively. [28] Analyzing the above literature, which indicated that the prodrug approach of coumarin and its derivatives designed to achieve a potent and selective inhibition against hCA IX and hCA XII is reported to have the 6 th and 7 th positions as the most favorable for substitutions as shown in structure I-VII whereas the substitutions at the 3 rd and 4 th positions coumarin ring from our previous work showed moderately active inhibition against cancer-associated isoforms hCA IX and hCA XII. In this work, we designed the new series of coumarin derivatives by moving the substitutions to the 6 th F I G U R E 1 Coumarin derivatives as selective human carbonic anhydrase (hCA) IX and hCA XII inhibitors.…”

mentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

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6‐Aminocoumarin oxime‐ether/sulfonamides as selective hCA IX and XII inhibitors: Synthesis, evaluation, and molecular dynamics studies

Ghouse

Sinha

Bonardi

et al. 2023

Archiv der Pharmazie

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Carbonic anhydrase isoforms IX and XII are overexpressed in hypoxic tumor cells regulating various physiological processes such as cell proliferation, invasion, and metastasis, resulting in the onset and spread of cancer. Selective inhibition of these enzymes is a promising strategy for anticancer therapy. Coumarin derivatives were identified as selective and potent inhibitors of these isoforms. This study reports 6‐aminocoumarin sulfonamide and oxime ether derivatives linked through a chloroacetyl moiety tethered to piperazine and piperidone, respectively, showing selective inhibition against human carbonic anhydrase (hCA) IX and XII with Ki ranging from 0.51 to 1.18 µM and 0.89–4.43 µM. While the sulfonamide derivative 8a exhibited submicromolar inhibition against hCA IX and XII with Ki 0.89 and 0.51 µM, the oxime ether derivatives showed lower activity than the sulfonamides, with the compound 5n inhibiting hCA IX and hCA XII with a Ki of 1.055 and 0.70 µM, respectively. The above results demonstrate the potential of these derivatives as selective, potent inhibitors of carbonic anhydrase IX and XII and provide a foundation for further optimization and development as effective anticancer agents. Further, the binding mode of the synthesized derivatives in the active site were examined using molecular docking and dynamic simulation studies.

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Section: Methodsmentioning

confidence: 99%

Section: In Silico Studiesmentioning

confidence: 99%

mentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

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6‐Aminocoumarin oxime‐ether/sulfonamides as selective hCA IX and XII inhibitors: Synthesis, evaluation, and molecular dynamics studies

Ghouse

Sinha

Bonardi

et al. 2023

Archiv der Pharmazie

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“…Over the past years, researchers have leveraged this privileged scaffold to design inhibitors incorporating diverse "tails," with the intention of identifying lead molecules, particularly for isoforms hCA IX and XII. [29][30][31][32][33] Numerous research groups have contributed to this endeavor, producing a significant body of literature demonstrating the efficacy and selectivity of these designed compounds in inhibiting these tumor-associated isoforms (hCA IX and/or XII) while differentiating them from the prevalent, cytosolic, and main offtarget isoforms, namely hCA I and II. [29][30][31][32][33] This approach not only underscores the potential of coumarin-based derivatives for targeted inhibition but also highlights their utility in addressing the challenge of isoform selectivity, a critical consideration in drug development.…”

Section: Introductionmentioning

confidence: 99%

Exploring the potency of diazo‐coumarin containing hybrid molecules: Selective inhibition of tumor‐associated carbonic anhydrase isoforms IX and XII

Yapar,

Lolak,

Bonardi

et al. 2024

ChemMedChem

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This study introduces a series of ten hybrid molecules DK(1‐10), which combine diazo and coumarin moieties along with diverse aromatic substitutions. The primary objective was to evaluate the inhibitory capabilities of these compounds against four prominent isoforms: the cytosolic hCA I and II, as well as the tumor‐associated membrane‐bound hCA IX and XII. Impressively, the majority of the tested compounds exhibited significant inhibition activity against the tumor‐associated isoforms hCA IX and XII, with KI values ranging from 29.2 to 293.3 nM. Notably, compound DK‐8 displayed particularly robust inhibitory activity against the tumor‐associated membrane‐bound isoforms, hCA IX and XII, yielding KI values of 32.5 and 29.2 nM, respectively. Additionally, another derivative, DK‐9, containing a primary sulfonamide, exhibited notable inhibition against hCA XII with a KI value of 36.4 nM. This investigation aimed to explore the structure‐activity relationships within these compounds, shedding light on how various substitutions and structural components influence their inhibitory potential. As a result, these compounds present promising candidates for further exploration in medicinal and pharmacological research. Their ability to selectively inhibit specific isoforms, particularly those associated with hypoxic tumors, suggests their potential as foundational compounds for the development of novel therapeutic agents.

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Tumor associated carbonic anhydrase inhibitors: Rational approaches, design strategies, structure activity relationship and mechanistic insights

Nerella,

Thacker,

Arifuddin

et al. 2024

European Journal of Medicinal Chemistry Reports

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Synthesis and biological evaluation of new 3-substituted coumarin derivatives as selective inhibitors of human carbonic anhydrase IX and XII

Cited by 9 publications

References 36 publications

6‐Aminocoumarin oxime‐ether/sulfonamides as selective hCA IX and XII inhibitors: Synthesis, evaluation, and molecular dynamics studies

6‐Aminocoumarin oxime‐ether/sulfonamides as selective hCA IX and XII inhibitors: Synthesis, evaluation, and molecular dynamics studies

Exploring the potency of diazo‐coumarin containing hybrid molecules: Selective inhibition of tumor‐associated carbonic anhydrase isoforms IX and XII

Tumor associated carbonic anhydrase inhibitors: Rational approaches, design strategies, structure activity relationship and mechanistic insights

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