1,5-Disubstituted Tetrazoles as Promising Anticancer Resistance Agents: A Chemoinformatic Characterization

The 1,5-disubstituted tetrazole (1,5-DS-T) scaffold is recognized as a privileged structure in medicinal chemistry due to its broad interaction potential with biologically relevant targets. In this study, we conducted an integrated chemoinformatic and molecular modeling analysis of 1,5-DS-T compounds from PubChem, ChEMBL, DrugBank, and an in-house library. Principal component analysis and scaffold diversity analyses showed that the in-house compounds occupy a region of chemical space largely overlapping with bioactive ChEMBL tetrazoles, while also revealing opportunities for further scaffold diversification. Analysis of pIC₅₀ values and annotated therapeutic targets highlighted the broad bioactivity profile of 1,5-DS-T across pharmacologically relevant protein classes. Ligand-based target prediction combined with k-means clustering suggested CXCR3, a chemokine receptor implicated in cancer drug resistance, as a plausible target for the in-house collection. Subsequent molecular docking studies prioritized IH-114 as the most promising computational hit, and Boltz-2 analysis supports the proposed CXCR3 binding. Finally, we found that only a small fraction of bioactive 1,5-DS-T compounds were synthesized via the Ugi-azide reaction, a modular chemical strategy, central to our research work. This highlights the need for further exploration and synthesis of new 1,5-disubstituted tetrazole-based scaffolds via isocyanide-based multicomponent reactions to explore new regions of the chemical space and discover novel drug candidates targeting chemoresistant diseases.