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A novel [3+3] annulation reaction of 2‐alkenylindoles with hydrazonyl chlorides in the presence of base for the formation of pyridazino[4,5‐b]indoles was developed. This approach provided a convenient and efficient way to synthesize a series of functionalized pyridazino[4,5‐b]indoles derivatives. The method exhibited a broad substrate scope and provided the corresponding pyridazino[4,5‐b]indoles products with excellent yields. [ABSTRACT FROM AUTHOR]

Pyridazino[4,5-b]indole is an important class of heterocyclic compounds with numerous applications in the field of medicinal chemistry. This review summarizes the synthetic methods of pyridazino[4,5-b]indoles published during the period from 1962 to 2022. In this review, we have discussed different methods for the synthesis of pyridazino[4,5-b]indole from various starting materials and the difficulties that scientists faced during the preparation process. We focus on the recent developments in synthetic methods of the pyridazino [4,5-b]indoles. [ABSTRACT FROM AUTHOR]

The nucleus of pyridazino[4,5-b]indoles contains two heterocyclic moieties that interact with many receptors. They are an important class of heterocyclic compounds with diverse applications in the field of medicinal chemistry. This review summarizes the reactions and biological importance of pyridazino[4,5-b] indoles during the period from 1962 to 2023. The reactions involve chlorination, hydrazinolysis, functionalization of pyridazino[4,5-b]indoles at positions 1, 2, or 5 and others dealing with reactions occuring at positions 1 and 3. This review article will include the latest advances on the applications of the pyridazino[4,5-b]indoles. [ABSTRACT FROM AUTHOR]

The alkylation of 3,5-dihydro-4H-pyridazino[4,5-b]indole-4-thione with benzyl bromide, ethyl chloroacetate, and allyl bromide in the presence of potassium carbonate (K2CO3) yielded new alkylsulfanylpyridazino[4,5-b]indole derivatives (i.e., compounds 4–6). Hydrazinolysis of ester 6 resulted in hydrazide 7. The structure of compound 6 was verified by X-ray single-crystal analysis. Among the synthesized compounds, compound 6 exhibited the most promising cytotoxicity toward MCF-7 cells with an IC50 value of 12 µM. It showed potential inhibition activity toward EGFR, PI3K, and AKT in MCF-7 cells, with 0.26-, 0.49-, and 0.31-fold reductions in concentration compared to an untreated control. Additionally, it showed apoptosis-inducing activity in MCF-7 cells (47.98-fold); overall apoptosis increased to 38.87% compared to 0.81% in the untreated control, which disrupted the cell cycle at pre-G1 and S phases. Moreover, compound 6 exhibited good binding affinities toward the tested proteins (EGFR, PI3K, and AKT) and had binding energies ranging from −15.87 to −24.87 Kcal/mol. It also formed good interactions with essential amino acids inside the binding sites. Hence, compound 6 is recommended as an anti-breast cancer chemotherapeutic due to its effects on the EGFR-PI3K-AKT pathway. [ABSTRACT FROM AUTHOR]

The alkylation of 3,5-dihydro-4H-pyridazino[4,5-b]indole-4-thione with benzyl bromide, ethyl chloroacetate, and allyl bromide in the presence of potassium carbonate (K2CO3) yielded new alkylsulfanylpyridazino[4,5-b]indole derivatives (i.e., compounds 4–6). Hydrazinolysis of ester 6 resulted in hydrazide 7. The structure of compound 6 was verified by X-ray single-crystal analysis. Among the synthesized compounds, compound 6 exhibited the most promising cytotoxicity toward MCF-7 cells with an IC50 value of 12 µM. It showed potential inhibition activity toward EGFR, PI3K, and AKT in MCF-7 cells, with 0.26-, 0.49-, and 0.31-fold reductions in concentration compared to an untreated control. Additionally, it showed apoptosis-inducing activity in MCF-7 cells (47.98-fold); overall apoptosis increased to 38.87% compared to 0.81% in the untreated control, which disrupted the cell cycle at pre-G1 and S phases. Moreover, compound 6 exhibited good binding affinities toward the tested proteins (EGFR, PI3K, and AKT) and had binding energies ranging from −15.87 to −24.87 Kcal/mol. It also formed good interactions with essential amino acids inside the binding sites. Hence, compound 6 is recommended as an anti-breast cancer chemotherapeutic due to its effects on the EGFR-PI3K-AKT pathway.

Synthesis and in vitro antimicrobial activities are reported for a series of 1,3,5-substituted 4-oxo-3,4-dihydro-5H-pyridazino[4,5-b]indole derivatives. Corresponding pyridazino[4,5-b]indoles were prepared from ethyl 3-formyl-1H-indole-2-carboxylate precursors and the functional group in question was installed with hydrazine and its derivatives. The purity and primary structures of pyridazino[4,5-b]indole were confirmed by IR, ¹H NMR, and 13CNMR spectroscopy and elemental analyses. All of the indoles were tested for in vitro antimicrobial activity against 8 isolates of bacteria and a fungus including Staphylococcus aureus NRRL B-767, Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Proteus vulgaris NRRL-B123, Salmonella typhimurium NRRL B-4420, Bacillus subtilis NRRL 744, Listeria monocytogenes ATCC 7644, and Candida albicans by using broth microdilution test. All of the isolates showed moderate sensitivity against tested indoles and B. subtilis NRRL 744 was the most sensitive. [ABSTRACT FROM AUTHOR]