Discovery of novel tetrahydrobenzo[b]thiophene-3-carbonitriles as histone deacetylase inhibitors

Gediya, Piyush A.; Vyas, Vivek K.; Carafa, Vincenzo; Sitwala, Nikum D.; Torre, Laura Della; Poziello, Angelita; Kurohara, Takashi; Suzuki, Takayoshi; Sanna, Vinod K.; Raguraman, Varalakshmi; Suthindhiran, K.; Ghosh, Debarpan; Bhatia, Dhiraj; Altucci, Lucia; Ghate, Manjunath

doi:10.1016/j.bioorg.2021.104801

Cited by 10 publications

(4 citation statements)

References 49 publications

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“…First, the aldol condensation reaction intermediates formed from acetophenones 1a – g and glyoxylic acid were treated with hydrazine hydrate (NH 2 NH 2 ·H 2 O) (99%) in a cyclization reaction to give 3-pyridazinone analogues 2a – g − (ketonic form), according to the enthalpy favor of tautomerization from 3-hydroxypyridazine to 3-pyrazidinone . Subsequently, chlorination of 2a – g was performed by the reflux in phosphorus oxychloride to produce 3-chloropyridazine derivatives 3a – g , which were heated in absolute ethanol (abs EtOH) with thiourea to attain 4a – g , as presented in Scheme . , On the other side, the 4-amino benzenesulfonamide 5 and 4-(2-aminoethyl)benzenesulfonamide 8 reacted with chloroacetyl chloride to afford the chloroacetamide derivatives 6 and 9 , respectively. , The target derivatives 7a – g and 10a – g were prepared by nucleophilic substitution reaction from reacting 4a – g with the appropriate chloroacetamide derivatives 6 and 9 in abs EtOH using sodium ethoxide (freshly prepared) as a base (Schemes and ).…”

Section: Resultsmentioning

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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Section: Resultsmentioning

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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“…The target derivatives 8a–f and 9a–f were prepared as outlined in Scheme . First, the reaction of different acetophenones 1a–f with glyoxylic acid was followed by treatment with hydrazine hydrate to afford 3-pyridazinone analogues 2a–f . − Moreover, reflux of 2a–f in phosphorous oxychloride resulted in 3-chloropyridazine analogues 3a–f that were reacted with thiourea in absolute ethanol to obtain 4a–f . , The one-pot Gewald reaction of three components, cyclic ketone (cyclopentanone 5a or cyclohexanone 5b ), malononitrile, and elemental sulfur, was used, using morpholine as a basic catalyst, to synthesize the predicted amines, 2-amino-3-cyanothiophene derivatives ( 6a and 6b ), then followed by the reaction of 6a and 6b with chloroacetylchloride to give the chloroacetamide derivatives 7a–b . , Targets 8a – f and 9a–f were prepared by the reaction of 4a–f with the appropriate chloroacetamide derivatives 7a–b in absolute ethanol in the presence of freshly prepared sodium ethoxide (Scheme ). All the final candidates 8a – f and 9a–f were characterized by 1 H NMR, 13 C NMR, mass, and elemental analyses.…”

Section: Resultsmentioning

confidence: 99%

Ligand-Based Design on the Dog-Bone-Shaped BIBR1532 Pharmacophoric Features and Synthesis of Novel Analogues as Promising Telomerase Inhibitors with In Vitro and In Vivo Evaluations

et al. 2022

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Telomerase is an outstanding biological target for cancer treatment. BIBR1532 is a non-nucleoside selective telomerase inhibitor; however, it experiences ineligible pharmacokinetics. Herein, we aimed to design new BIBR1532-based analogues as promising telomerase inhibitors. Therefore, two novel series of pyridazine-linked to cyclopenta[b]thiophene (8a−f) and tetrahydro-1-benzothiophene (9a−f) were synthesized. A quantitative real-time polymerase chain reaction was utilized to investigate the telomerase inhibitory activity of candidates. Notably, 8e and 9e exhibited the best inhibition profiles. Moreover, 8e showed strong antitumor effects against both MCF-7 and A549 cancer cell lines. The effects of 8e on the cell cycle and apoptosis were measured. Besides, 8e was evaluated for its in vivo antitumor activity using solid Ehrlich carcinoma. The reduction in both the tumor weight and volume was greater than doxorubicin. Also, molecular docking and ADME studies were performed. Finally, a SAR study was conducted to gain further insights into the different telomerase inhibition potentials upon variable structural modifications.

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“…[102] In 2021, Gediya et al designed novel compounds as HDAC inhibitors bearing the 2-aminotetrahydrobenzo[b]thiophene-3carbonitrile moiety. [103] The design of this study is based on pharmacophore modeling. Two series differ in the linker, either piperazine or piperidine were synthesized.…”

Section: Histone Deacetylase (Hdac) Inhibitorsmentioning

confidence: 99%

A decade's overview of 2‐aminothiophenes and their fused analogs as promising anticancer agents

Darwish,

El‐Sherief,

Abdel‐Aziz

et al. 2024

Archiv der Pharmazie

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Over the past decades, cancer has been a challenging domain for medicinal chemists as it is an international health concern. In association, small molecules such as 2‐aminothiophenes and their derivatives showed significant antitumor activity through variable modes of action. Therefore, this article aims to review the advances regarding these core scaffolds over the past 10 years, where 2‐aminothiophenes and their fused analogs are classified and discussed according to their biological activity and mode of action, in the interest of boosting new design pathways for medicinal chemists to develop targeted antitumor candidates.

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Discovery of novel tetrahydrobenzo[b]thiophene-3-carbonitriles as histone deacetylase inhibitors

Cited by 10 publications

References 49 publications

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

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

Ligand-Based Design on the Dog-Bone-Shaped BIBR1532 Pharmacophoric Features and Synthesis of Novel Analogues as Promising Telomerase Inhibitors with In Vitro and In Vivo Evaluations

A decade's overview of 2‐aminothiophenes and their fused analogs as promising anticancer agents

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