Rafaqat Hussain

Microsized polystyrene (PS, <5 µm) acts as a carrier of toxic metals, like arsenic (As), and poses a serious threat. The complicated surface chemistry of the micro PS+As contaminants makes it challenging to remove. Herein, we report a versatile adsorbent, KOH‐activated magnetic carbon and metal‐organic framework hybrid material (MCK6@MOF) for the removal of micro PS+As contaminants from aqueous systems. The hybrid MCK6@MOF, synthesized through a room‐temperature approach tailored with diverse functionalities, adsorbs PS+As toxic contaminants with ∼100% efficiency within 15 min at ambient conditions. The presence of As with PS alters its surface charge and accelerates adsorption, reducing the adsorption time for the PS+As by four times. Adsorption studies for complex‐contaminated systems demonstrate that the presence of metals (As(III), Cr(III), Cu(II)) in an aqueous environment with PS microplastics alters the surface charge of the adsorbent, resulting in 98% adsorption of PS within 15 min. Ex situ analysis confirms that electrostatic attraction, π‐π interaction, hydrogen bonding and surface complexation are the driving adsorption mechanisms. MCK6@MOF retains removal efficiency of 96% for the PS+As complex over multiple cycles. The regeneration process resulted in ∼10% mass loss of the adsorbent, indicating partial deterioration of the material structure.

The ongoing prevalence of SARS-CoV-2 variations highlights the urgent need for novel antiviral agents targeting key viral proteins. The papain-like protease (PLpro) is pivotal in viral replication and immune evasion, rendering it a compelling therapeutic target. In the present study, a series of novel thiadiazole- and oxadiazole-based derivatives (12-g & 13a-g) were rationally designed based on the structural features of the known PLpro inhibitor GRL0617. Convergent synthetic strategy was employed to synthesize the target compounds involving the construction of 1,3,4-thiadiazole/oxadiazole intermediates followed by amide coupling with a naphthyl-containing scaffold. All compounds were characterized by ¹ H NHMR, ¹³ C NMR and mass spectrometry and evaluated for their in vitro SARS-CoV-2 PLpro inhibitory activity. Several compounds exhibited potent inhibition, surpassing the reference inhibitor GRL0617 (IC ₅₀ = 2.4 ± 1.1 µM). Among them, oxadiazole derivative (13c) featuring 3-cyanophenyl substitution emerged as the most potent inhibitor with IC ₅₀ value of 0.06 ± 0.8 µM, followed by compounds (12b, IC ₅₀ = 0.3 ± 0.3 µM), (12e, IC ₅₀ = 0.4 ± 1.6 µM) and (13e, IC ₅₀ = 0.6 ± 0.8 µM) respectively. Structure activity relationship (SAR) analysis revealed that electron-withdrawing substituents, particularly cyano group at meta position, significantly enhanced PLpro inhibition whereas methoxy/methyl groups resulted in reduced inhibition. Furthermore, molecular docking studies demonstrated favorable binding interactions of the compounds within the PLpro catalytic pocket through H-bonding, hydrophobic and π–π interactions. Moreover, molecular dynamic simulations confirmed the stability of the ligand-protein complexes throughout the simulation period supporting the experimental findings. The integrated rational design-based synthesis, biological evaluation, and computational investigations collectively identified thiadiazole/oxadiazole scaffolds as promising candidates for the development of SARS-CoV-2 inhibitors, offering valuable insights for next-generation antiviral agents targeting coronavirus proteases.

The papain-like protease (PLpro) of SARS-CoV-2 plays a key role in viral polyprotein processing and suppression of host innate response, making it a valuable target for development of anti-viral drugs. However, the availability of potent small-molecule SARS-CoV-2 PLpro inhibitors remains limited. In this study, a novel series of compounds based on ([ ]-N-(1-(naphthalen-1-yl)ethyl)benzamide bearing thiadiazole/oxadiazole (14a-14g and 15a-15g) scaffolds have been designed and synthesized as novel SARS-CoV-2 (PLpro) inhibitors. The synthesized compounds were characterized using ¹ H NMR, [ ]C NMR, and HRMS and then evaluated for in vitro enzymatic inhibition against SARS-CoV-2 (PLpro). Several compounds demonstrated moderate to potent SARS-CoV-2 (PLpro) inhibition, with IC[ ] values in the range of [ ]M to [ ]M. The obtained results were compared to standard inhibitor GRL0617 (IC[ ]M). Specifically, compounds 15c (IC[ ]M), 14a(IC[ ]M), 14g (IC[ ]M), 14c (IC[ ]M), and 15a (IC[ ]M) were found to be more potent against SARS-CoV-2 (PLpro), even more active than standard inhibitor. Structure–activity relationship (SAR) evaluation showed that the inhibitory potency is mainly influenced by the substitution pattern of the aryl moiety attached to the thiadiazole/oxadiazole motif. The molecular docking study of the most active compound 15c demonstrated a favorable binding conformation within the SARS-CoV-2 PLpro, highlighted by stable hydrogen bonding and hydrophobic interactions with key catalytic residues, thereby enhancing inhibitory potency. Additionally, density functional theory (DFT) calculations and in silico ADMET analyses of potent compound 15cindicated favorable electronic behavior and provided preliminary insight into its pharmacokinetic and safety characteristics, thereby supporting its potential for further structural optimization. Altogether, these findings identify lead compound 15c as a promising tool for further optimization and development of new and improved SARS-CoV-2 (PLpro) inhibitors for combating COVID-19.

The papain-like protease (PL[ ] of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) plays a key role in viral polyprotein processing and suppression of host innate response, making it a valuable target for the development of anti-viral drugs. However, the availability of potent small-molecule inhibitors of PL[ ] remains limited. The current study was designed to synthesize novel indole-tagged thia/oxadiazole scaffolds (10–23) and their inhibition profile against PL[ ] was tested, with GRL0617 used as a reference inhibitor. The evaluation revealed a broad spectrum of inhibitory potency, with IC[ ] values ranging from 0.7934 [ ]M to 23.79 [ ]M. Remarkably, compounds 13 (IC[ ] 0.7934 [ ]M), 11 (IC[ ] 1.118 [ ]M), and 18 (IC[ ] 1.446 [ ]M) demonstrated superior inhibitory potency relative to the reference inhibitor GRL0617 (IC[ ] 2.40 [ ]M). Based on structure–activity relationship (SAR) investigations, the alterations to the aryl ring substituents attached to the thia/oxadiazole scaffold were identified to be the key factor for modulating inhibitory potency. The molecular docking study of the most active compound 13 demonstrated a favorable binding conformation within the PL[ ], highlighted by stable hydrogen bonding and hydrophobic interactions with key catalytic residues, thereby enhancing inhibitory potency. Additionally, Density Functional Theory (DFT) calculations and Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) analyses of potent compound 13 showed favorable electronic properties and suitable pharmacokinetic properties, supporting its potential for further optimization. Altogether, these findings identify compound 13 as a potent early-stage enzymatic hit that provides a valuable starting point for further structural optimization toward the development of improved SARS-CoV-2 PL[ ] inhibitors.

The ongoing COVID-19 pandemic has presented enormous challenges to worldwide healthcare systems, and effective therapeutic strategies must accompany mass vaccination efforts. In this context, Mpro (the main protease of SARS-CoV-2) is arguably one of the most promising molecular targets for antiviral drug development because it is responsible for processing viral polyproteins and replicating the virus. In this study, a rational design approach was employed to develop a novel series of thiadiazole-based derivatives as potential Mpro inhibitors. A total of compounds ( 5a–f , 9a–d , and 12a–j ) were synthesized through three systematically organized synthetic schemes. Each stage of the design strategy incorporated progressive structural modifications to establish a clear structure activity relationship (SAR) and enhance inhibitory potency. The synthesized compounds were evaluated for their in vitro inhibitory activity against SARS-CoV-2 Mpro. Some derivatives like 5b (IC ₅₀ = 44.63 ± 1.20 µM), 12c (IC ₅₀ = 39.25 ± 1.60 μM), 12a (IC ₅₀ = 41.93 ± 1.90 μM), showed good inhibitory activity as compared to reference drug Nirmatrelvir (IC ₅₀ = 58.4 ± 8.6 μM). Molecular docking analysis supported the experimental data by confirming stable binding of the synthesized compounds within the Mpro active site through key hydrogen-bonding and hydrophobic interactions.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder associated with cholinergic dysfunction. We report a novel series of pyrazolo[3,4-[ ]] pyrimidine–thiadiazole derivatives as dual inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The compounds were characterized by ¹ H NMR, [ ]C NMR, and HRMS, and their inhibitory activity was evaluated in vitro. Among the synthesized series, compound 10f emerged as the potent analogue, exhibiting [ ] values of 14.60 ± 1.80 nM (AChE) and 290.76 ± 2.90 nM (BuChE), with inhibitory potency comparable to the reference drug Donepezil. Molecular docking revealed that these compounds engage in both catalytic and peripheral anionic sites via [ ]–[ ] stacking and hydrogen-bond interactions, supporting a dual-binding mechanism. Density functional theory (DFT) calculations at the B3LYP/6-31G(d,p) level highlighted electronic features correlating with activity, while in silico ADMET profiling suggested favorable oral bioavailability and low toxicity. These results position this series as promising multifunctional lead candidates for further development in AD therapy.