| Summary: | 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 (K<sub>2</sub>CO<sub>3</sub>) yielded new alkylsulfanylpyridazino[4,5-b]indole derivatives (i.e., compounds <b>4</b>–<b>6</b>). Hydrazinolysis of ester <b>6</b> resulted in hydrazide <b>7</b>. The structure of compound <b>6</b> was verified by X-ray single-crystal analysis. Among the synthesized compounds, compound <b>6</b> exhibited the most promising cytotoxicity toward MCF-7 cells with an IC<sub>50</sub> 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 <b>6</b> 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 <b>6</b> is recommended as an anti-breast cancer chemotherapeutic due to its effects on the EGFR-PI3K-AKT pathway.
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