Anna Claudia Cunha

Indole and its derivatives represent a crucial class of heterocyclic compounds with broad applications in pharmaceuticals, agrochemicals, and materials science. The indole core is a fundamental structural motif in numerous biologically active natural products, including alkaloids, as well as synthetic molecules exhibiting diverse pharmacological properties such as anticancer, antimicrobial, anti‐inflammatory, and antiviral activities. This review concisely addresses the biosynthesis of the indole nucleus and highlights several noteworthy derivatives, including tryptophan, indigo, and indole‐3‐carbinol, among others. It explores the chemistry of indole derivatives, emphasizing their multidisciplinary relevance, and substantial impact across various fields of scientific research. Furthermore, the review discusses both classical and contemporary synthetic methodologies for constructing the indole framework, with an emphasis on sustainable approaches aligned with green chemistry principles.

This review provides a comprehensive overview of research on 1,2,4‐triazoles conducted over the last fifteen years. 1,2,4‐Triazoles are highly significant in the pharmaceutical industry, with numerous compounds from this class used clinically as antifungal, antiviral, antibacterial, anti‐inflammatory, and antitubercular agents. Beyond their pharmaceutical relevance, this review also explores their role in material science and agriculture. In material science, 1,2,4‐triazoles are gaining prominence, particularly in the development of energetic materials (EMs), due to their exceptional properties such as thermal stability, coordination ability, and performance comparable to well‐known explosives. Their applications extend to polymers, corrosion inhibitors, and metal‐organic frameworks (MOFs), and they play a significant role in the development of functional materials for sensors, catalysis, and energy storage. Additionally, the review addresses general aspects and synthetic methodologies for the functionalization and construction of the 1,2,4‐triazole ring. Synthetic methods discussed include metalation synthesis, cyclization of hydrazine derivatives, multicomponent reactions, cyclization of amides and amidines, and microwave‐assisted synthesis. Given the significance of the triazole scaffold, its synthesis has garnered considerable attention due to its wide‐ranging applications across various industrial sectors.

Aim: This work describes the synthesis and antimicrobial evaluation of 6-aminated 1,4-benzoquinones (6-AQs) against seven resistant pathogens. Materials & methods: The 6-AQs, synthesized via a Michael addition reaction between bromoquinone and p-substituted anilines, were assessed for their antimicrobial activity through both in vitro and in silico analyses. Results: Bromoquinone and 6-AQs with electron-withdrawing groups demonstrated activity against Pseudomonas aeruginosa, with minimum inhibitory concentrations ranging from 16 to 128 mu g/ml, comparable to standard antimicrobials. Two derivatives exhibited minimum inhibitory concentrations values against methicillin-resistant Staphylococcus aureus ranging from 64 to 128 mu g/ml. These compounds demonstrated both bacteriostatic and bactericidal effects, and antibiofilm features. Conclusion: The 6-AQs 19g and 19f showed a promising antimicrobial profile, indicating their potential as new therapeutic options.

Two different products were obtained by the regiodivergent reaction of benzoquinone derivatives with phenolates and anilines: 3-aryloxybenzoquinone and 2-phenylamino-3-bromobenzoquinone. Calculated density functional theory free energies of reaction values corroborate the experimental observation of the formation of the substitution product in the reaction with phenolates in acetonitrile and the product of addition/oxidation for the reaction with aniline in water. Calculated charges and Fukui functions are similar for C2 and C3 atoms, indicating an equal possibility to suffer a nucleophilic attack. The calculated energy barriers for nucleophilic attack steps indicated that the first steps of the substitution with phenolates and addition/oxidation with anilines are faster, which justifies the formation of the respective products. The natural bond order analysis for the transition states revealed that there is a strong interaction between lone pairs of N and O atoms and the pi C2C3* for the O -> C2 and N -> C3 attacks and a weak interaction for the O -> C3 and N -> C2 attacks, which also agrees with experimental observations.

Imatinib (IMT) is the first-in-class BCR-ABL commercial tyrosine kinase inhibitor (TKI). However, the resistance and toxicity associated with the use of IMT highlight the importance of the search for new TKIs. In this context, heterocyclic systems, such as quinoline, which is present as a pharmacophore in the structure of the TKI inhibitor bosutinib (BST), have been widely applied. Thus, this work aimed to obtain new hybrids of imatinib containing quinoline moieties and evaluate them against K562 cells. The compounds were synthesized with a high purity degree. Among the produced molecules, the inhibitor 4-methyl-N3-(4-(pyridin-3-yl)pyrimidin-2-yl)-N1-(quinolin-4-yl)benzene-1,3-diamine (2g) showed a suitable reduction in cell viability, with a CC₅₀ value of 0.9 µM (IMT, CC₅₀ = 0.08 µM). Molecular docking results suggest that the interaction between the most active inhibitor 2g and the BCR-ABL1 enzyme occurs at the bosutinib binding site through a competitive inhibition mechanism. Despite being less potent and selective than IMT, 2g is a suitable prototype for use in the search for new drugs against chronic myeloid leukemia (CML), especially in patients with acquired resistance to IMT.

This article presents a comprehensive overview of multicomponent reactions (MCRs) that proceed via ortho‐quinone methide intermediates (o‐QM) generated in the reaction medium. Examples of applications involving these highly reactive intermediates in organic synthesis and biological processes (e. g., biosynthetic pathways, prodrug cleavage and electrophilic capture of biological nucleophiles) are also described. QMs are often generated by eliminative processes of phenol derivatives or by photochemical reactions, including reversible generation in photochromic substances. This class of compounds can undergo various reaction types, including nucleophilic attack at the methide carbon, with subsequent rearomatization, and react with electron‐rich dienophiles in inverse‐electron demand hetero‐Diels‐Alder reactions. Its versatile reactivity has been explored in the context of cascade reactions for the construction of several classes of substances, including complex natural products.

The enzyme tyrosine kinase BCR-Abl-1 is the main molecular target in the treatment of chronic myeloid leukemia and can be competitively inhibited by tyrosine kinase inhibitors such as imatinib. New potential competitive inhibitors were synthesized using the (phenylamino)pyrimidine-pyridine (PAPP) group as a pharmacophoric fragment, and these compounds were biologically evaluated. The synthesis of twelve new compounds was performed in three steps and assisted by microwave irradiation in a 1,3-dipolar cycloaddition to obtain 1,2,3-triazole derivatives substituted on carbon C-4 of the triazole nucleus. All compounds were evaluated for their inhibitory activities against a chronic myeloid leukemia cell line (K562) that expresses the enzyme tyrosine kinase BCR-Abl-1 and against healthy cells (WSS-1) to observe their selectivity. Three compounds showed promising results, with IC₅₀ values between 1.0 and 7.3 μM, and were subjected to molecular docking studies. The results suggest that such compounds can interact at the same binding site as imatinib, probably sharing a competitive inhibition mechanism. One compound showed the greatest interaction affinity for BCR-Abl-1 in the docking studies.