Cesar Augusto Roque-Borda

Molecular hybridization represents a promising strategy in drug‐design and the discovery of novel biologically active molecules, as it can enhance molecular affinity and potency while simultaneously reducing resistance and side effects. This review explores the recent advancements in the design, synthesis, and biological evaluation of hybrid molecules that combine sulfonamide with thiazolidinone or thiazolidine‐2,4‐dione scaffolds. The review covered studies published from 2009 to 2025 and focused exclusively on compounds containing both a sulfonamide moiety and a thiazolidinone or thiazolidinedione framework in the same molecule. These hybrid compounds have attracted considerable attention due to their potential to address the complexity of multifactorial diseases such as cancer, infections, and metabolic disorders, which often involve multiple biological pathways. By integrating features from both sulfonamides and thiazolidines, researchers have developed molecules with enhanced pharmacological profiles, including improved antimicrobial, anticancer, anti‐inflammatory, antidiabetic, and anticonvulsant activities. The review highlights how these hybrids often display multitarget effects, making them promising candidates for overcoming limitations of traditional single‐target drugs, such as resistance and limited efficacy. Key findings from recent studies are summarized, with a focus on the structural aspects that contribute to biological activity. Sulfonamide–thiazolidinone and sulfonamide–thiazolidinedione hybrids represent a versatile and valuable strategy in the search for new treatments for complex diseases.

Rifampicin-resistant TB should be integrated into the global AMR response through diagnostics, surveillance, and optimized treatment regimens.

Efflux pumps are widely viewed as antibiotic resistance determinants, yet their roles in stress adaptation, virulence, quorum sensing, and biofilm formation make them context-dependent therapeutic targets. This Perspective distinguishes four efflux intervention strategies: direct inhibition, bioenergetic or membrane-mediated suppression, regulatory modulation, and dual-effect approaches. We examine why promising in vitro findings rarely translate clinically and argue that efflux-targeting strategies require defined therapeutic objectives and integrated multidisciplinary approaches.

Polysaccharide–peptide conjugates are modular biomaterials that combine hydrated carbohydrate frameworks with peptide domains capable of mediating molecular recognition, degradability, antimicrobial activity, and biological signaling. In this review, we discuss how covalent, bioorthogonal, and enzymatic conjugation strategies regulate peptide density, orientation, accessibility, and stability within polysaccharide-based matrices. These chemical choices are analyzed in relation to network architecture, viscoelasticity, ligand presentation, degradation behavior, and cell–material interactions. Representative systems based on hyaluronic acid, alginate, chitosan, dextran, cellulose, and glycosaminoglycans are examined to illustrate how peptide functionalization can transform otherwise passive scaffolds into adhesive, degradable, antimicrobial, or therapeutically responsive platforms. We further highlight dynamic and enzyme-responsive materials, localized drug delivery systems, antimicrobial coatings, and antibiofilm interfaces as key biomedical applications of these conjugates. The review also addresses translational challenges associated with structural heterogeneity, stability, immunogenicity, sterilization, batch-to-batch reproducibility, and clinical feasibility. Taken together, the evidence discussed here indicates that the performance of polysaccharide–peptide conjugates depends on reproducible structure–function relationships linking conjugation chemistry, macromolecular architecture, and biological activity under application-relevant conditions.

ESKAPE pathogens represent a priority clinical threat due to their multidrug-resistance, persistence in biofilms, and ability to evade antibiotic therapy. In response to these limitations, antimicrobial peptides (AMPs) have emerged as promising platforms for the development of novel anti-infective strategies. This review analyzes the potential of AMPs against ESKAPE pathogens, integrating their main classes, mechanisms of action, design strategies, and barriers to clinical translation. Natural, synthetic, and peptidomimetic AMPs are examined, along with lytic mechanisms, intracellular targets, anti-virulence effects, quorum quenching, and immunomodulation. In addition, in silico design approaches, multi-objective prediction, and molecular optimization strategies—including stereochemical modifications, cyclization, lipidation, PEGylation, and hybrid design—are discussed. Finally, their activity against ESKAPE biofilms is addressed, together with current limitations related to stability, toxicity, delivery, and preclinical validation.

SUMMARY: Multidrug-resistant (MDR) bacterial infections continue to outpace therapeutic innovation, undermining the efficacy of conventional antibiotics and exposing the limitations of the current drug pipeline. In this review, we critically examine the translational viability of peptide-based antimicrobials and siderophore conjugates—two classes of therapeutics often promoted as next-generation solutions against MDR pathogens. Rather than reiterating their mechanistic promise, we dissect the structural assumptions that underpin their design and expose the clinical blind spots that have hindered their success. While peptides offer membrane disruption, intracellular targeting, and, in some cases, selective bacterial killing, their efficacy remains context-dependent and is frequently compromised by host-driven proteolysis, poor bioavailability, and limited tissue penetration. Similarly, siderophore-based conjugates exploit iron uptake systems for targeted delivery, yet depend on bacterial receptors that are variably expressed, easily suppressed, or genetically lost during infection. The failure of cefiderocol in specific clinical settings exemplifies the vulnerability of “Trojan horse” approaches to metabolic plasticity and ecological interference. This review highlights the need for a paradigm shift—from broad biochemical optimism to receptor-aware, pathogen-stratified, and pharmacologically grounded strategies. Reframing these modalities within their biological and clinical constraints offers a more realistic foundation for the development of actionable peptide- and siderophore-based therapies against resistant bacterial infections.

Peptide lipidation is widely employed to enhance the apparent biological performance of peptide-based systems by improving stability, membrane association, and systemic persistence. However, increased potency is often interpreted uncritically as evidence of improved molecular design. This Perspective highlights that lipidation can reshape peptide behaviour by partially shifting functional control from sequence-encoded molecular recognition toward context-dependent effects in which membrane interactions, carrier binding, supramolecular assembly, and residence time play an increasingly important role. Under such design-dependent conditions, enhanced activity may primarily reflect delivery- and exposure-driven amplification rather than improved intrinsic efficacy. While MIC values and endpoint assays remain valuable benchmarks of activity, they are insufficient on their own to guide rational optimization of lipidated peptides, as they conflate intrinsic activity with lipid-driven distribution and time-dependent effects. Accordingly, this Perspective argues not against lipidation itself, but for reframing lipidation as a deliberately controllable interaction element rather than a generic potency modifier, thereby restoring mechanistic interpretability and design robustness in peptide chemical biology.

Antimicrobial peptides (AMPs) have re-emerged as promising anti-infective agents, particularly against multidrug-resistant bacteria; however, their therapeutic development remains constrained by proteolytic degradation, host cell toxicity, and rapid systemic clearance. Rather than focusing solely on sequence discovery, recent efforts have shifted toward structural and supramolecular modification strategies aimed at improving stability, selectivity, and pharmacological performance. This review critically analyzes intramolecular modifications—including phosphorylation, glycosylation, acetylation, methylation, and backbone cyclization—that modulate peptide conformation and resistance to enzymatic degradation. In parallel, extramolecular approaches such as PEGylation, lipidation, and conjugation to antibiotics, siderophores, or antibodies are examined in the context of enhanced targeting and prolonged bioavailability. Particular emphasis is placed on localized delivery systems, including hydrogels, polymeric films, and nanofibrous scaffolds, which enable spatially controlled administration and mitigate systemic exposure. By integrating evidence from ex vivo and in vivo infection models, this work delineates the translational potential and remaining bottlenecks of chemically engineered AMP platforms for skin and soft tissue infections.

Antimicrobial resistance (AMR) has emerged as one of the most critical global health challenges, undermining the clinical efficacy of existing antibiotics and threatening modern therapeutic strategies. The ongoing misuse and overuse of antimicrobial agents have accelerated the evolution of resistant bacterial strains and parasites, underscoring the need to discover new molecules with enhanced potency and selectivity. Quinoxaline derivatives, a versatile class of nitrogen‐containing heterocycles, have attracted significant attention for their broad‐spectrum antimicrobial and antiparasitic activities owing to their tunable electronic properties and structural flexibility. This review provides a comprehensive and up‐to‐date overview of the chemistry, structure–activity relationships (SARs), and biological mechanisms of quinoxaline‐based compounds, offering novel SAR insights that extend and refine those presented in previous quinoxaline reviews. Unique to this manuscript is the explicit cross‐comparison of SAR trends across a diverse set of studies, highlighting both consensus and divergence in how key substituent classes—including halogens, N‐oxides, and cationic or hybrid frameworks—influence activity profiles against bacteria, fungi, and parasites. Mechanistic targets such as DNA gyrase, dihydrofolate reductase (DHFR), and membrane disruption are discussed with attention to how scaffold tuning enables novel modes of action. By consolidating advances in synthetic chemistry, mechanistic understanding, and rational scaffold optimization, this review demonstrates the broad therapeutic potential of quinoxaline frameworks and provides guidance for the development of next‐generation antimicrobial and antiparasitic agents to address the growing threat of AMR.

Pyrazole-thiazole hybrids 1-(a-k) were synthesized and fully characterized to investigate their biological activities against Trypanosoma cruzi and Mycobacterium tuberculosis . Physicochemical profiling confirmed favorable drug-like properties across the series. Biological assays identified compound 1g (3-F) as the most active against T. cruzi, with IC₅₀ values of 11.66 μM (SI > 42.8) in trypomastigotes and 26.83 μM (SI > 18.9) in amastigotes. Compound 1h (4-Br) displayed significant antimycobacterial activity, with a MIC of 32.28 μM against the H37Rv strain. In silico analyses suggested preferential stabilization of halogenated derivatives through hydrophobic and π-driven interactions in structurally related enzymatic pockets, used here as an exploratory model. Taken together, these findings demonstrate that halogen substitution strongly modulates affinity and biological performance, supporting pyrazole-thiazole hybrids as promising scaffolds for further optimization against neglected-parasite pathogens. Future studies expanding halogen patterns and probing alternative binding pockets may improve potency and target selectivity across this chemical space.