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Somatostatin receptor-4 (SST₄) is a therapeutic target for several conditions, including Alzheimer's disease, seizures, neuropsychiatric disorders, and pain. Our previous work on 1,2,4-triazole derivatives led to enhanced SST₄ binding affinity, selectivity, and functional activity. Herein we report the discovery of 3-thio-1,2,4-triazole series as selective and high affinity SST₄ agonists. Thirty-three compounds show <100 nM binding affinity, five of which had sub-nanomolar binding affinity and >300-fold selectivity over other SST subtypes. SST₄ cAMP inhibition assay activity data aligned with the ligand binding affinity. Comparative docking results of the ligands under investigation with the cryo-EM and most recent model-built SST₄ structures suggest similar trends in binding. Amino acids responsible for high and moderate affinity were identified, whereas poorer ligand conformations and limited interactions were observed with the low-affinity compounds. In summary, this study presents a novel series of high affinity SST₄ agonists with corresponding in vitro activity, demonstrating viable therapeutic potential.

Irreversible targeted covalent inhibitors, in the past regarded as inappropriately reactive and toxic, have seen a recent resurgence in clinical interest. This paradigm shift is attributed to the exploitation of the two-step mechanism, in which a high affinity and selectivity (i.e., low K_I) scaffold binds the target and only then does a pendant low intrinsic reactivity warhead react with the target (moderate k_inact). This highlights the importance of evaluating inhibitors by deriving both their K_I and k_inact values. The development of methods to evaluate these inhibitors by accounting for their time-dependent nature has been crucial to the discovery of promising clinical candidates. Herein, we report all the practical kinetic methods available to date to derive k_inact and K_I values. These methods include direct observation of covalent modification, continuous assay (Kitz & Wilson) evaluation, and discontinuous incubation and pre-incubation time-dependent IC₅₀ assays. We also provide practical guidelines and examples for performing these assays, comparison of their utility, and perspectives for their extended applications. This review aims to provide clarity about the use of these methods for reporting complete inhibitor kinetic profiles, guiding irreversible drug development towards increased target affinity and selectivity, while modulating in vivo stability and on-target reactivity.

The emergence of the mobile colistin resistance (mcr) gene is a demonstrable threat contributing to the worldwide antibiotic resistance crisis. The gene is encoded on plasmids and can easily spread between different bacterial strains. mcr encodes a phosphoethanolamine (pEtN) transferase, which catalyses the transfer of the pEtN moiety from phosphatidylethanolamine to lipid A, the head group of lipopolysaccharides (LPS). This neutralises the overall negative charge of the LPS and prevents the binding of polymyxins to bacterial membranes. We believe that the development of polymyxin adjuvants could be a promising approach to prolong the use of this important class of last-resort antibiotics. This review discusses recent progress in the identification, design and development of adjuvants to restore polymyxin sensitivity in these resistant bacteria, and focuses on both MCR inhibitors as well as alternative approaches that modulate polymyxin resistance.

Thiophene is a privileged pharmacophore in medicinal chemistry owing to its diversified biological attributes. The thiophene moiety has been ranked 4th in the US FDA drug approval of small drug molecules, with around 7 drug approvals over the last decade. The present review covers USFDA-approved drugs possessing a thiophene ring system. Our analysis reveals that 26 drugs possessing thiophene nuclei have been approved under different pharmacological classes. The review further covers reported thiophene and its substituted analogues with diverse biological activities, including anti-diabetic, anticancer, anti-inflammatory, anticonvulsant, and antioxidant activity. Besides, a section is dedicated to appreciating the implications of structural bioinformatics in drug discovery. Additionally, the manuscript delves into structure–activity relationship studies to explore the chemical groups responsible for eliciting potential therapeutic activities. The review may provide invaluable insights for researchers working with thiophene nuclei in developing novel analogues with greater efficacy and fewer side effects.

The development of H₂S-donating derivatives of non-steroidal anti-inflammatory drugs (NSAIDs) is considered important to reduce or overcome their gastrointestinal side effects. Sulforaphane, one of the most extensively studied isothiocyanates (ITCs), effectively releases H₂S at a slow rate. Thus, we rationally designed, synthesized, and characterized new ITC derivatives (I1–3 and I1a–e) inspired by the natural compound sulforaphane. The anti-inflammatory properties of these compounds were evaluated by their inhibitory activities against cyclooxygenase targets COX-1 and COX-2. Additionally, the cytotoxicity of the compounds was tested using the MTT assay on LPS-induced RAW 264.7 cells, revealing no cytotoxic effects at low doses. Notably, compounds I1 and fluorine-containing ester derivative I1c emerged as the most potent and selective COX-2 inhibitors, with selectivity indexes of 2611.5 and 2582.4, respectively. The H₂S-releasing capacities of ITC derivatives were investigated and compared with that of sulforaphane, showing that while compounds I1–3 exhibit slow and similar H₂S release to sulforaphane, the release from compounds I1a–e was not as pronounced as that of the standard. Physics-based molecular modeling studies including molecular docking and molecular dynamics (MD) simulations, binding free energy calculations and absorption, distribution, metabolism, and excretion (ADME) analyses were also conducted. MD simulations analysis underscored the crucial amino acids such as Tyr385, Trp387, Phe518, Val523, and Ser530 in the interactions between I1c hit compound and COX-2. The combined in silico and in vitro findings suggest that compounds I1 and I1c are promising NSAID candidates against selective COX-2 inhibition.

Exploring new inhibitors with good bioavailability and high selectivity for managing type 2 diabetes mellitus (T2DM) and its associated complications is a major challenge for research, academia, and the pharmaceutical industry. Protein tyrosine phosphatase-1B (PTP1B) arose as an important negative regulator in insulin signaling pathways associated with metabolic disorders, including T2DM and obesity. Novel neutral compounds with a benzene-sulfonamide scaffold were designed and synthesized based on structural- and ligand-based drug design strategies for fragment growth. Promising hits against PTP1B were identified through in vitro enzymology inhibition assay. Mechanistic aspects of the compound's different inhibition activities were rigorously investigated through molecular docking coupled with explicit dynamics simulations. Four identified hits, 3c, 8, 10a, and 11, with sub-micromolar PTP-1B IC₅₀ and significant predicted pharmacokinetic and pharmacodynamic parameters, were further biologically evaluated for their anti-diabetic, anti-obesity, anti-inflammatory, and anti-oxidant effects in a high-fat diet (HFD) + streptozotocin (STZ)-induced T2DM rat model. All these hit compounds exhibited a significant anti-diabetic and anti-obesity effect and a significant efficacy in reducing oxidative stress and increasing anti-oxidant enzymes while reducing inflammatory markers. Improving compound potency was further highlighted by improving the pharmacokinetic profile of the most active compound, 10a, through nano formulation. Compound 10a nano formulation showed the most promising anti-diabetic and anti-obesity effects and a remarkable histopathological improvement in all organs studied.

In our continued efforts to tackle antibiotic resistance, a new series of pyrazole–ciprofloxacin hybrids were designed, synthesized, and evaluated for their antibacterial activity against Staphylococcus aureus (S. aureus), Pseudomonas aeruginosa (P. aeruginosa), and Mycobacterium tuberculosis (Mtb). Most of the compounds exhibited good to excellent activities against S. aureus, and six compounds (7a, 7b, 7d, 7g, 7k, and 7p) exhibited higher or comparable activity (MIC = 0.125–0.5 μg mL⁻¹) to ciprofloxacin (0.125 μg mL⁻¹). Further, these selected compounds were non-toxic (CC₅₀ ≥ 1000 μg mL⁻¹) when evaluated for cell viability test against the Hep-G2 cell line. Three compounds (7a, 7d, and 7g) demonstrated excellent activity against ciprofloxacin-resistant S. aureus with MIC values ranging from 0.125–0.5 μg mL⁻¹ and good antibiofilm activity. Among them, 7g displayed remarkable antibiofilm activity with an MBIC₅₀ value of 0.02 μg mL⁻¹, which is 50 times lower than ciprofloxacin (MBIC₅₀ = 1.06 μg mL⁻¹). A time-kill kinetics study indicated that 7g showed both concentration and time-dependent bactericidal properties. In addition, 7g effectively inhibited DNA-gyrase supercoiling activity at 1 μg mL⁻¹ (8× MIC). Two compounds 7b and 7d exhibited the highest activity against Mtb with a MIC of 0.5 μg mL⁻¹, while 7c showed the highest activity against P. aeruginosa with a MIC value of 2 μg mL⁻¹. Molecular docking studies revealed that 7g formed stable interactions at the DNA active site.

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The development of chemical scaffolds that target highly conserved MALAT1 RNA received attention due to its significance in splicing, nuclear organization, and gene expression in disease progression pathways. Here, we synthesized a series of N-fused quinazolino-quinazoline-diones via a PIDA-induced C–N coupling methodology to target MALAT1. Interestingly, compound 2z binds to the UUG pocket of a MALAT1 RNA triple-helix through intercalation, evidenced from molecular docking studies, fluorescence-based assay and CD experiments. 2z exhibited cytotoxicity towards MALAT1 overexpressing cancer cells (SKOV-3, IC₅₀ of 8.0 ± 0.4 μM). These findings demonstrated 2z as a MALAT1 RNA triple-helix intercalator with therapeutic potential, offering an important chemical scaffold to understand MALAT1 activity in disease development pathways.

The evolution of antimicrobial-resistant strains jeopardizes the existing clinical drugs and demands new therapeutic interventions. Herein, we report the synthesis of cationic thiazolidine bearing a quaternary pyridinium group, in which thiazolidine was N-acylated with fatty acid to establish a hydrophilic–lipophilic balance that disrupts bacterial membranes. The bacterial growth inhibition assays and hemolytic activity against human red blood cells indicate that the N-acylated cationic thiazolidine (QPyNATh) inhibits Gram-positive bacteria at lower minimum inhibitory concentrations (MIC) and is selective for bacteria over mammalian cells. N-Acylation modulates MIC, and it is found that the N-palmitoylated compound, QPyN16Th, had the lowest MIC (1.95 μM) against Gram-positive, Enterococcus faecalis, Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA). In contrast, the N-myristoylated compound, QPyN14Th, showed the lowest MIC (31.25 μM) against Gram-negative, Escherichia coli, uropathogenic Escherichia coli, and Pseudomonas aeruginosa. At 1× MIC, QPyNATh permeabilizes the bacterial membrane, depolarizes the cytoplasmic membranes, and produces excess reactive oxygen species to kill the bacteria, as evidenced by live and dead staining. Interestingly, only QPyNATh containing a palmitoyl acyl chain demonstrated membrane-damaging activity at 2 μM concentrations, suggesting that the optimal hydrophilic–lipophilic balance enables QPyN16Th to selectively kill Gram-positive bacteria at lower doses. S. aureus develops resistance to ciprofloxacin quickly; however, no resistance to QPyN16Th is observed after several passages. As a proof of concept, the animal study revealed that QPyN16Th treatment reduced the bacterial burden in MRSA-infected zebrafish, allowing them to recover from infection and resume normal life. The results imply that lipidation and derivatizing thiazolidine with cationic charge offer an antimicrobial that is selective to treat Gram-positive bacterial infections, biocompatible, and less prone to develop resistance.