Novel annulated thiophene derivatives: Synthesis, spectroscopic, X-ray, Hirshfeld surface analysis, DFT, biological, cytotoxic and molecular docking studies

Author: Sayed, Galal H. ; Kozakiewicz-Piekarz, Anna ; Anwer, Kurls E. ; Ramadan, Ramadan M.

Ethyl-2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate as a precursor derivative was used for the synthesis of variable heterocyclic compounds through its reactions with different reagents such as 9-anthraldehyde, 4-acetylbiphenyl, Et chloroacetate, Et benzoylacetate, chloroacetonitrile and di-Et malonate.Both conventional thermal and microwave irradiation techniques were used in the synthetic procedures.Mol. formulas and structures of the obtained derivatives were elucidated using different anal. and spectroscopic tools such as IR, ¹H-, ¹³C-NMR as well as mass spectrometry.Variable structure features were observed for the products.The structure and crystal surface anal. of ethyl-2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate were also obtained from the X-ray diffraction and Hirshfeld studies.Energy optimized structures of the reported compounds were performed by d. functional theory (DFT/B3LYP) with the basis set 6-31 G and double zeta plus polarization (d,p).Quantum reactivity descriptors were calculated and correlated with their biol. properties.The reported derivatives were analyzed for antimicrobial and cytotoxic inhibitions.The mol. docking studies of compounds were investigated as well.Structure and activity relationship of the reported compounds were correlated with the data of antimicrobial and cytotoxicity activity.

12 Jan 2023·ACS Medicinal Chemistry Letters

Thienopyrimidine Derivatives as GPR55 Receptor Antagonists: Insight into Structure–Activity Relationship

Article

Author: Sayed, Sommayah S. ; Morales, Paula ; Reggio, Patricia H. ; Abood, Mary E. ; Fernández-Ruiz, Javier ; Gómez-Cañas, María ; Jagerovic, Nadine ; Croatt, Mitchell P. ; Colón, Katsuya L. ; Zhao, Pingwei ; Figuerola-Asencio, Laura ; Hurst, Dow P.

GPR55 is an orphan G-protein coupled receptor involved in various pathophysiological conditions. However, there are only a few noncannabinoid GPR55 ligands reported so far. The lack of potent and selective GPR55 ligands precludes a deep exploration of this receptor. The studies presented here focused on a thienopyrimidine scaffold based on the GPR55 antagonist ML192, previously discovered by high-throughput screening. The GPR55 activities of the new synthesized compounds were assessed using β-arrestin recruitment assays in Chinese hamster ovary cells overexpressing human GPR55. Some derivatives were identified as GPR55 antagonists with functional efficacy and selectivity versus CB1 and CB2 cannabinoid receptors.

10 Jan 2019·Journal of Medicinal ChemistryQ1 · MEDICINE

A Thieno[2,3-d]pyrimidine Scaffold Is a Novel Negative Allosteric Modulator of the Dopamine D₂ Receptor

Q1 · MEDICINE

Article

Author: Mistry, Shailesh N. ; Zarzycka, Barbara ; Lim, Herman D. ; Kellam, Barrie ; Capuano, Ben ; Fyfe, Tim J. ; Scammells, Peter J. ; Lane, J. Robert ; Katrich, Vsevolod

Recently, a novel negative allosteric modulator (NAM) of the D₂-like dopamine receptors 1 was identified through virtual ligand screening. This ligand comprises a thieno[2,3- d]pyrimidine scaffold that does not feature in known dopaminergic ligands. Herein, we provide pharmacological validation of an allosteric mode of action for 1, revealing that it is a NAM of dopamine efficacy and identify the structural determinants of this allostery. We find that key structural moieties are important for functional affinity and negative cooperativity, while functionalization of the thienopyrimidine at the 5- and 6-positions results in analogues with divergent cooperativity profiles. Successive compound iterations have yielded analogues exhibiting a 10-fold improvement in functional affinity, as well as enhanced negative cooperativity with dopamine affinity and efficacy. Furthermore, our study reveals a fragment-like core that maintains low μM affinity and robust negative cooperativity with markedly improved ligand efficiency.

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Indication	Highest Phase	Country/Location	Organization	Date
Hyperlipidemias	Phase 1	India	Zydus Lifesciences Ltd.	-
Hyperlipidemias	Phase 1	-	Zydus Cadila Healthcare Ltd.	-

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