Synthesis and biological activity of conformationally restricted indole-based inhibitors of neurotropic alphavirus replication: Generation of a three-dimensional pharmacophore

Barraza, Scott J.; Sindac, Janice A.; Dobry, Craig J.; Delekta, Philip C.; Lee, Pil; Miller, David J.; Larsen, Scott D.

doi:10.1016/j.bmcl.2021.128171

Cited by 3 publications

(4 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Overall, results were revealed that the substitution of indole motif and electron-donating group at C-5 on ring indole could be advantageous for neuroprotective activities. Larsen and co-workers [117] reported the design and synthesis of novel substituted indole (78) derivatives and evaluated the inhibitory activity of neurotropic alphavirus replication. From, the SAR studies the compound (R)-1-(1-(4chlorobenzyl)-1H-indole-2-carbonyl)-N-(1-phenylethyl) piperidine-4-carboxamide displayed more potent inhibitory activity.…”

Section: Alzheimer's Disease Activitymentioning

confidence: 99%

The Multi‐Pharmacological Targeted Role of Indole and its Derivatives: A review

Mathada¹,

Yernale

Basha³

2023

ChemistrySelect

View full text Add to dashboard Cite

Heterocycles are a privileged motif that appears as a momentous objective in medicinal chemistry. An important class of compounds for drug discovery and design is indole and its derivatives, which have been examined for a variety of biological activities. Therefore, it is noteworthy in the modern progress of synthetic, medicinal chemistry; the last decade has been onlooker with a multitude of reports on several indole derivatives corroborating these chemical entities to be a renowned target for the discovery of new drugs. The current study includes brief natural sources of indole, and a new range of commercially available indole‐based drugs. Additionally, this review discusses the numerous facets of the structure‐activity relationship study (SARs) and provides information about the varied pharmacological effects of indole derivatives. The literature data presented for the anti‐pharmacological agents herein covers largely from the year 2015 to mid of 2022.

show abstract

Section: Alzheimer's Disease Activitymentioning

confidence: 99%

The Multi‐Pharmacological Targeted Role of Indole and its Derivatives: A review

Mathada¹,

Yernale

Basha³

2023

ChemistrySelect

View full text Add to dashboard Cite

show abstract

“…A series of indole 2-carboxamides, represented by compound 2 ( Figure 12 , Table 4 ), was described previously [ 182 ] with activity against WEEV in a replicon assay (IC 50 = 0.5 µM, CC 50 = 65 µM); however, the precise mechanism of action regarding the target and how the compounds may bind was unknown. Conformationally restricted indole 2-carboxamides were synthesized to improve potency against WEEV and define a pharmacophoric model [ 183 ]. Though significant gains in potency were not achieved compared to compound 2, dihydroindene 12 showed comparable potency against WEEV without notable cytotoxicity (IC 50 = 0.53 µM, CC 50 > 100 µM).…”

Section: Additional Small Molecule Inhibitors Of Encephalitic Alphavi...mentioning

confidence: 99%

“…Though significant gains in potency were not achieved compared to compound 2, dihydroindene 12 showed comparable potency against WEEV without notable cytotoxicity (IC 50 = 0.53 µM, CC 50 > 100 µM). Scaffold rigidification and SAR, with computational analysis, refined a pharmacophoric model for this chemotype [ 183 ].…”

Section: Additional Small Molecule Inhibitors Of Encephalitic Alphavi...mentioning

confidence: 99%

Advances in the Development of Small Molecule Antivirals against Equine Encephalitic Viruses

Ogorek

Golden

2023

Viruses

View full text Add to dashboard Cite

Venezuelan, western, and eastern equine encephalitic alphaviruses (VEEV, WEEV, and EEEV, respectively) are arboviruses that are highly pathogenic to equines and cause significant harm to infected humans. Currently, human alphavirus infection and the resulting diseases caused by them are unmitigated due to the absence of approved vaccines or therapeutics for general use. These circumstances, combined with the unpredictability of outbreaks—as exemplified by a 2019 EEE surge in the United States that claimed 19 patient lives—emphasize the risks posed by these viruses, especially for aerosolized VEEV and EEEV which are potential biothreats. Herein, small molecule inhibitors of VEEV, WEEV, and EEEV are reviewed that have been identified or advanced in the last five years since a comprehensive review was last performed. We organize structures according to host- versus virus-targeted mechanisms, highlight cellular and animal data that are milestones in the development pipeline, and provide a perspective on key considerations for the progression of compounds at early and later stages of advancement.

show abstract

“…Nevertheless, the substrate acceptance of the existing engineered AmDH toolbox toward the structurally diverse target fused-ring and linked-ring aryl ketones is still limited, whereas the corresponding arylamines are recurrent building blocks in a large number of enzyme inhibitors, antagonists, and agonists (Figure S1). − Although substantial attention has been focused on the synthetic applications of these complex arylamines, to the best of our knowledge, no prior work has systematically explored the synthesis of these arylamines via AmDH-catalyzed amination.…”

Section: Introductionmentioning

confidence: 99%

Shield Machine-like Substrate Walking Strategy-Based Pocket Engineering of F-Amine Dehydrogenase for Accessing Structurally Diverse Fused-Ring and Linked-Ring Aryl Ketones

Wu,

Xu,

Nie

et al. 2024

ACS Catal.

View full text Add to dashboard Cite

Although amine dehydrogenases (AmDHs) are emerging as attractive biocatalysts for chiral amine synthesis, their synthetic application in structurally diverse arylamines remains challenging, given the limited substrate acceptance. Substrate walking is an effective coevolution strategy to confer targeted substrate acceptance to an enzyme through a stepwise mutagenesis landscape adaptation. Here, based on the conventional substrate walking strategy, we report a shield machine-like substrate walking strategy to quickly evolve F-BbAmDH from Bacillus badius for accessing the difficult-to-aminate fused-ring and linked-ring aryl ketones. A set of monoring aryl ketone homologues with the benzene ring located at the end of the side-chain and regularly extended carbon skeletons was rationally selected as the transition substrates. A superior mutant library with expanded target fused-ring and linked-ring aryl ketone acceptance was identified based on the activity and specificity enhancement of the transition substrates, enabling the synthesis of pharmaceuticals and bioactive compound-related arylamines with up to 94% yield and 99% ee (R) or 99:1 cis/trans. Structure-based computational results provided molecular insights into the source of the expanded substrate acceptance. Our work demonstrates a concise engineering workflow for the collective acceptance evolution of enzymes for structurally diverse substrate panels and has promising prospects in enzyme engineering.

show abstract

Synthesis and biological activity of conformationally restricted indole-based inhibitors of neurotropic alphavirus replication: Generation of a three-dimensional pharmacophore

Cited by 3 publications

References 43 publications

The Multi‐Pharmacological Targeted Role of Indole and its Derivatives: A review

The Multi‐Pharmacological Targeted Role of Indole and its Derivatives: A review

Advances in the Development of Small Molecule Antivirals against Equine Encephalitic Viruses

Shield Machine-like Substrate Walking Strategy-Based Pocket Engineering of F-Amine Dehydrogenase for Accessing Structurally Diverse Fused-Ring and Linked-Ring Aryl Ketones

Contact Info

Product

Resources

About