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The therapy to treat the Human Immunodeficiency virus (HIV) and decrease the viral load has been a challenge since its discovery due to its ability to mutate, escape from drug therapies, and immunologic system. Consequently, the development of new therapies, especially potential molecules that focus on specific viral mechanisms to block viral replication, became a critical challenge in recent decades. The Reverse Transcriptase (RT) is an RNA- and DNA-dependent DNA polymerase enzyme that is responsible for transcribing viral RNA into double-stranded DNA. Non-nucleoside RT Inhibitors perform important role in HIV therapy, and they are responsible for inhibiting RT by blocking its allosteric site, which shows physico-chemical properties such as high hydrophobicity and key amino acid-to-hydrogen bond interactions. For this reason, designing new molecules with innovative heterocycles compatible with these characteristics can provide new potential inhibitors. For example, pentacyclic heterocycles like thiazole and its derivatives like thiazolidinedione, which have physico-chemical properties that can interact with the allosteric site of RT, can be a new perspective in designing new Non-nucleoside RT Inhibitors. This work reviews the scientific literature concerning these compounds and can help the design of new antiviral therapeutics.

The concept of “undruggable” targets has long represented a major limitation in medicinal chemistry, referring to proteins and biomolecules that lack well-defined binding pockets or exhibit highly dynamic conformational behavior. However, advances in structural biology, chemical biology, and computational methodologies are rapidly expanding the scope of tractable therapeutic space. Emerging modalities, including targeted protein degradation, molecular glues, macrocycles, RNA-targeting small molecules, covalent ligands, and artificial intelligence-assisted molecular design, enable pharmacological mechanisms beyond classical occupancy-based inhibition through strategies such as induced proximity, expanded molecular recognition, covalent engagement, and RNA-level regulation. These approaches challenge the traditional binary classification of druggability and support a more context-dependent view of therapeutic accessibility. Despite this progress, significant challenges remain in optimizing pharmacokinetic properties, ensuring selectivity, minimizing toxicity, and achieving robust clinical translation. This editorial provides a mechanistic perspective on how emerging modalities are extending the boundaries of modern drug discovery.

The target-oriented synthesis of diethylene glycol-linked bis-imidazo- and bis-thiazolo ring-fused mono-, bi-, and tricyclic derivatives was accomplished using inexpensive reagents, bis-phenacyl bromide derivative 4, and thiosemicarbazone 6. The diethylene glycol-linked architectures included bis(thiazolo[3,2-a]pyrimidinone) derivatives 8a,b, bis(imidazo-azole) derivatives 12-14, bis(imidazo-thiazole) derivatives 17,18, and bis-thiazoles 20a-g. Cytotoxic evaluation against liver, lung, colon, and prostate human tumor cell lines found remarkable selectivity to hepatocellular carcinoma (HepG2) cells. The most potent bis-imidazo- and bis-thiazolo-fused derivatives 8a,b, 12 and 13 demonstrated cytotoxicity against HepG2 cells (IC₅₀ 6.8–17.8 µM) with exceptional selectivity (SI 5.6–14.6) compared with cisplatin (SI 2.4). Further screening of their VEGFR-2 TK and FGFR-2 TK inhibition showed that 8a had moderate activity, whereas phenyl-substituted derivative 8b displayed promising anti-VEGFR-2 and remarkable anti-FGFR-2 activities, with IC₅₀ 0.19 ± 0.01 and 0.03 ± 0.01 µM, respectively, compared with the reference drugs sorafenib (IC₅₀ 0.12 ± 0.01) and staurosporine (IC₅₀ 0.03 ± 0.01 µM). The inhibition of VEGFR-2 and FGFR-2 TKs was supported by molecular docking studies, with compound 8b showing binding affinity to the VEGFR-2 and FGFR-2 ATP binding pockets. Pharmacokinetics and ADMET drug-likeness evaluation indicated that bis(thiazolo[3,2-a]pyrimidinone) derivatives 8a and 8b have drug-like properties.

Human coronaviruses include both endemic respiratory pathogens and highly pathogenic viruses with pandemic potential, underscoring the need for antiviral agents with activity beyond single viral species. This review focuses on selected, representative antiviral inhibitors directed against viral proteins of human coronaviruses. Accordingly, the review examines representative inhibitors targeting viral proteins essential for coronavirus infection and propagation. The discussion includes inhibitors acting at different functional levels of the viral life cycle, such as entry, genome replication, RNA processing and particle assembly, and reflects the range of molecular entities reported to date. By organizing known inhibitors according to their viral protein targets, this review provides an integrated overview of current antiviral candidates and illustrates the central role of viral proteins as points of intervention. Overall, the review aims to consolidate existing knowledge on antiviral inhibitors across human coronaviruses, offering a coherent framework for appreciating their scope and diversity.

Cysteine proteases are recognized as relevant therapeutic targets in both parasitic diseases and cancer due to their essential biological functions. Among these enzymes, cruzain from Trypanosoma cruzi is an important molecular target for the treatment of Chagas disease. Likewise, human cathepsin L (hCatL) is a potential target for anticancer drug development. Both enzymes share conserved catalytic features, particularly the cysteine–histidine catalytic dyad, which enables interaction with nitrile-based reversible covalent inhibitors. Here, six nitrile-derived inhibitors (Neq1171.1, Neq1172.1, Neq1181.1, Neq1182.1, Neq1268, and Neq1276) had their cruzain and hCatL inhibition constants, K_i, determined. Besides, we have used molecular dynamics simulation and alchemical free energy calculations for evaluating the overall relative binding free energies of these inhibitors. The calculated free energy differences closely reproduced experimental trends, confirming the reliability of the computational protocol. These findings demonstrate that thermodynamic integration is an effective strategy for predicting relative binding affinities and provides valuable molecular-level insights for the rational optimization of cysteine protease inhibitors with potential applications in Chagas disease and cancer therapy.

Leishmania infantum trypanothione reductase (Li-TryR) is an essential enzyme for parasite redox homeostasis and a validated target for antileishmanial therapy. Classical inhibitors acting at the active site have shown limited success due to poor selectivity, suboptimal pharmacological properties, and lack of in-cell efficacy. This work presents a comprehensive strategy to develop first-in-class Li-TryR dimerization disruptors, targeting the protein–protein interface required for enzymatic activity. Through molecular modeling, mutagenesis, and structural analysis, a key α-helical hotspot (around residue E436) was identified as a druggable region. Interface-derived peptides, helix-stabilized stapled analogs, α/β-foldamers, and cell-penetrating conjugates demonstrated that dimer disruption effectively inhibits LiTryR and can translate into antiparasitic activity. Building on these insights, several families of small-molecule proteomimetics, including imidazole-phenyl-thiazoles, triazole analogs, and triazolium salts, were developed, achieving low-micromolar to submicromolar inhibition and significant activity in parasite cultures and intracellular models. Overall, this work establishes dimer-interface targeting as a novel therapeutic paradigm for leishmaniasis and provides multiple optimized chemical scaffolds for future drug development.

Due to the lack of metallo-β-lactamase (MβL) inhibitors for clinical purposes, the antibiotic resistance mediated by MβL poses a clear threat to public health. In this work, twelve symmetrical o-methylpyridine substituted tertiary amines P1–P6 and their Dy(III) complexes D1–D6 were synthesized, characterized, and confirmed. Nine compounds displayed inhibitory activity against MβLs from subclasses B1, B2, and B3. Encouragingly, D2 and D6 exhibited dual inhibitory activity targeting both imipenem-hydrolyzing MβL S (ImiS) and MβL L1 (L1). Mechanistic studies uncovered P2 exerted a competitive inhibition mode on New Delhi MβL-1 (NDM-1), while D6 showed a noncompetitive inhibition mode against ImiS and L1. Microbiological assays indicated the obtained inhibitors could restore the antibacterial activity of cefazolin and meropenem against six bacterial strains, including resistant ones, while P4, D1, and D6 alone exhibited bactericidal effect. Cytotoxicity assays showed the tested inhibitors performed a reasonable biological toxicity against L929 cells. Docking simulation reveals a molecular-level rationale for the dual-target inhibitory activity of D2, indicating the introduction of Dy(III) can regulate the inhibitory activity against both ImiS and L1. In short, the study demonstrate o-methylpyridine substituted tertiary amines and their Dy(III) complexes are promising scaffolds for the development of MβLs inhibitors and antibacterial agents.

Due to Pseudomonas aeruginosa (P. aeruginosa)’s inherent resistance to many antibiotics and the increasing incidence of multidrug-resistant (MDR) organisms, P. aeruginosa infection has become a growing global threat to humanity. Azithromycin (AZM) does not have prominent antibacterial activity against P. aeruginosa at a clinically reasonable level because of the bacteria’s outer membrane and efflux pump system; however, it does demonstrate other properties, including reduction of inflammation and suppression of P. aeruginosa virulence. With the promising potential of AZM as an anti-P. aeruginosa active compound, we proposed the application of a Trojan horse strategy to the synthesis of AZM derivatives. In this study, we designed and synthesized catechol-conjugated AZM derivatives and evaluated their anti-P. aeruginosa activity. One of the derivatives showed superior antibacterial activity to AZM, even against MDR P. aeruginosa clinical isolates.

Cannabidiol (CBD) and cannabigerol (CBG) are nonpsychotomimetic phytocannabinoids with neuroprotective properties. We have previously reported that CBD and CBG, but not their acidic forms, protect cerebellar granule neurons from rotenone-induced toxicity. These effects were independent of canonical (i.e., cannabinoid 1 and 2-receptors) and noncanonical cannabinoid targets (i.e., transient-receptor potential vanilloid type 1 or peroxisome proliferator-activated receptor), suggesting alternative mechanisms. The sigma-1 receptor (σ1R), a chaperone enriched at mitochondria-associated membranes, regulates Ca²⁺ homeostasis, oxidative stress, and mitochondrial function, representing a neuroprotective target. In this study, we investigated the role of σ1R in the neuroprotective actions of CBD and CBG using a rotenone-induced neurotoxicity model in primary neuronal cultures. Pharmacological blockade of σ1R with NE-100 abolished the neuroprotective effects of both cannabinoids, supporting a σ1R-dependent mechanism. Consistently, molecular docking and molecular dynamics simulations using the human σ1R structure revealed stable binding of CBD and CBG within the ligand-binding pocket, involving key residues for receptor recognition. According to the in vitro data, neutral forms showed higher predicted affinities than their acidic counterparts, while NE-100 exhibited the strongest binding. These findings identify σ1R as a functionally relevant target for CBD and CBG, supporting their neuroprotective effects through modulation of σ1R-mediated responses.

A series of pyrazolyl-thioureas was designed and synthesized as novel sirtuin 1 (SIRT1) and sirtuin 2 (SIRT2) inhibitors. Compounds were prepared through a multistep, divergent procedure starting from amino pyrazole intermediates. Biological evaluation revealed that several derivatives exhibited significant SIRT2 inhibitory activity, with compounds 6a and 7f emerging as the most promising inhibitors, showing IC₅₀ values of 2.2 and 13.6 µM, respectively. Selected compounds displayed selective antiproliferative activity against HepG2 hepatocellular carcinoma cells, while showing limited cytotoxicity toward normal fibroblasts. The biological properties of 6a and 7f were further investigated by analyzing SIRT1 activity and correlating antiproliferative activity with tubulin acetylation. Docking simulations identified the molecular basis of SIRT1 and SIRT2 inhibition. Overall, these results identify pyrazolyl thioureas as a promising scaffold for novel SIRT1 and SIRT2 inhibitors with potential anticancer applications.