Natural products remain privileged starting points in drug discovery because of their structural complexity, stereochemical richness, and bioactive scaffolds. Semisynthesis enables the transformation of natural products or naturally occurring precursors into structurally modified analogs, helping overcome limitations in supply, physicochemical properties, toxicity, or pharmacokinetic behavior. In this context, isocyanide-based multicomponent reactions (I-MCRs) provide rapid, modular, and operationally simple synthetic tools for the diversification of natural product-derived substrates. This review summarizes the application of I-MCRs in natural product semisynthesis, including Ugi four-component reactions (U-4CR), Passerini three-component reactions (P-3CRs), Groebke–Blackburn–Bienaymé three-component reactions (GBB-3CRs), Ugi–azide four-component reactions (UA-4CRs), and other related I-MCRs. The collected literature indicates that U-4CR is the most-explored MCR, whereas P-3CRs, GBB-3CRs, and, particularly, the UA-4CRs remain underexplored. A chemoinformatic characterization of 162 semisynthetic I-MCR products revealed that these compounds occupy a chemical space comparable to that of FDA-approved natural product-derived drugs, while retaining natural product-like complexity and three-dimensionality. In addition, molecular docking against CXCR3 was performed as a hypothesis-generating approach to prioritize candidates for further biological evaluation. These findings highlight I-MCRs as promising synthetic tools for expanding natural product-related chemical space and generating structurally novel semisynthetic analogs.

In this work, we report an efficient synthetic strategy for accessing novel 1,4-disubstituted-1,2,3-triazole-1,3-oxazole hybrids. The synthesis involves a two-step, three-sequence approach: a multicomponent reaction, subsequent oxidation, and the Van Leusen reaction. This operationally simple protocol proceeds under mild reaction conditions and allows the rapid assembly of structurally diverse heterocyclic systems. Three new hybrid molecules were synthesized and structurally characterized. To investigate their biological potential, we performed bioactivity prediction studies using cheminformatics tools. Polo-like kinase 3 (PLK3), a serine/threonine-protein kinase involved in cell cycle regulation and apoptosis, was identified as a potential molecular target, for which docking studies were performed, obtaining good ligand efficiency.

Tuberculosis remains a major global health problem, and the emergence of drug-resistant strains of Mycobacterium tuberculosis has intensified the search for new chemical entities with potential antimycobacterial activity. In this context, benzofuran derivatives represent attractive heterocyclic scaffolds in medicinal chemistry owing to their structural versatility and broad biological relevance. Herein, we report the synthesis and preliminary in silico evaluation of a small series of ten benzofuran ester imine derivatives designed as potential antitubercular agents. The target compounds were obtained in 45–89% yields via a Schiff base condensation reaction between an amino-benzofuran ester and benzaldehyde derivatives bearing substituents with varying electronic and steric properties. Notably, the products were isolated without column chromatography, highlighting the operational simplicity of the synthetic protocol. To complement the synthetic work, the benzofuran ester imines were evaluated using PASS online to estimate their probable biological activity spectrum. The prediction suggested potential antimycobacterial activity, supporting their further analysis through structure-based computational studies. Molecular docking was subsequently performed against the ATPase domain of mycobacterial DNA gyrase B (GyrB) using the crystallographic structure from Mycobacterium smegmatis deposited in the Protein Data Bank under accession code 4B6C. In general, the docking analysis showed favorable theoretical binding energies and plausible binding modes within the active site, with non-covalent interactions that may contribute to ligand stabilization.