Yasinalli Tamboli

1. Voltage-gated calcium channels permit the depolarization-induced entry of calcium ions into electrically excitable cells such as neurons and cardiac myocytes [1]. Among the family of voltage-gat...

We have authored a compelling and timely review that highlights the transformative potential of high-content imaging for discovering small molecules (SMs). SMs are crucial for advancing drug potency, selectivity, and precision, and their assessment through specialized cellular assays accelerates drug development. High-content imaging (HCI), which seamlessly integrates automated microscopy with sophisticated image analysis powered by artificial intelligence (AI), is revolutionizing cell-based assays by enabling a comprehensive evaluation of cellular parameters following drug treatment. The rich multivariate data generated by HCI from multiplexed assays unlock unprecedented insights into the cellular and subcellular effects of lead compounds, making it an indispensable tool in modern drug discovery.

In this work, we investigated the ability of pyrrolidine-appended quinoline derivatives to inhibit αamylase and α-glucosidase, two important targets for the treatment of type 2 diabetes. Compounds 4a-c were synthesized using two bioactive pharmacophores, 1-(2-chloroacetyl)pyrrolidine-2-carbonitrile 2 and substituted quinolines, and were subsequently characterized. Using acarbose as a standard, the compounds were evaluated for their ability to inhibit α-glucosidase and α-amylase. A detailed in silico analysis, including density functional theory (DFT) studies, molecular docking, and molecular dynamics simulations, was carried out to supplement the experimental results. According to the findings, compound 4b demonstrated encouraging in vitro inhibitory activity against α-glucosidase (IC50 = 41.06 ± 1.73 µg/mL) and α-amylase (IC50 = 22.84 ± 0.32 µg/mL), and was slightly less potent than acarbose, indicating its potential as a dual inhibitor. The compound can be further optimized and developed for clinical applications.

Voltage‐gated ion channels play important physiological roles by regulating the electrical activity of a range of different cell types through maintaining the gradients of different ions. Among these, voltage‐gated calcium channels mediate various cellular activities, including muscle contraction, gene regulation, and neurotransmission. A sub‐type of calcium channels are T‐type calcium channels that play a critical role in regulating neuronal excitability and are essential for neurodevelopment. Mutations in genes encoding T‐type calcium channels, including CACNA1G , CACNA1H , and CACNA1I can lead to altered channel activity, resulting in disrupted calcium entry, calcium signaling, synaptic plasticity, and neuronal differentiation. They have been implicated in a range of neurodevelopmental disorders, such as epilepsy, autism spectrum disorder, and intellectual disability. There has been considerable interest in developing blockers against T‐type calcium channels to restore the dysregulated calcium homeostasis in neuronal disorders. T‐type calcium channel blockers, originally developed for cardiovascular diseases, have emerged as potential therapeutic agents for neurodevelopmental disorders by targeting aberrant calcium signaling. This review explores the molecular mechanisms underlying T‐type channel dysfunction caused by genetic mutations and evaluates the current evidence on the therapeutic efficacy of T‐type calcium channel blockers in neurodevelopmental disorders. Although preclinical studies show promise, translating these findings into effective clinical therapies presents significant challenges. Future research focusing on optimizing blocker specificity and understanding the broader impact of channel modulation is necessary for developing targeted treatments for neurological pathologies.

Furo[2,3- c ]quinolone derivatives ( 3a–z ′) exhibit anti-cancer activity and represent ideal structural frameworks for therapeutic development.

Recently, quinoline has emerged as a critical heterocyclic structure, attracting attention for its diverse industrial and synthetic organic chemistry applications. This compound is essential for developing novel lead compounds in drug discovery and is extensively studied for its therapeutic derivatives in medicinal chemistry. An extensive body of literature details the methodologies for synthesizing this key scaffold and its functionalization to enhance biological efficacy. Numerous synthesis protocols have been documented, highlighting the significance of quinoline in ongoing chemical research. These methodologies include various strategies, such as transition metal‐catalyzed reactions and environmentally sustainable processes, which are crucial for constructing and functionalizing quinoline and its derivatives. This review aims to systematically examine the synthesis procedures and findings, addressing the limitations of these pathways and their environmental impacts. Additionally, a curated selection of quinolines and their derivatives will be presented.

A series of 2,4‐dichloro‐5‐{[4‐(phenylsulfonyl)piperazin‐1‐yl]carbonyl}benzenesulfonamides were designed and synthesized through amidation of Lasamide 1 with substituted piperazines. The newly obtained compounds demonstrated remarkable inhibition potency and selectivity for the human (h) expressed Carbonic Anhydrase (CA; EC 4.2.1.1) II isoform. Selected compounds 7 and 9 were investigated in an in vivo model of glaucoma and showed relevant performances, with the latter being able to last the effect up to 4 hours. The results herein reported are in sustainment of Lasamide derivatives as a new class of compounds potentially exploitable for the management of uncontrolled intra ocular pressure (IOP).

Lasamide is a synthetic precursor and a contaminant of the diuretic Furosemide manufacturing process and represents a highly valuable building block for fragment-based drug discovery approaches. We assessed the ability of Lasamide to inhibit in vitro the human-expressed Carbonic Anhydrases by means of the stopped-flow technique, and we assessed its binding modes within hCAs II and XII-mimic catalytic clefts by X-ray crystallography. Interestingly, an unprecedented crystal form for the hCA IX mimic H-tag is reported and discussed herein.