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The treatment of many bacterial diseases remains a significant problem due to the increasing antibiotic resistance of their infectious agents. Among others, this is related to <i>Staphylococcus aureus</i>, especially methicillin-resistant <i>S. aureus</i> (MRSA) and <i>Mycobacterium tuberculosis</i>. In the present article, we report on antibacterial compounds with activity against both <i>S. aureus</i> and MRSA. A straightforward approach to 2-(1<i>H</i>-indol-3-yl)quinazolin-4(3<i>H</i>)-one and their analogues was developed. Their structural and functional relationships were also considered. The antimicrobial activity of the synthesized compounds against <i>Mycobacterium tuberculosis</i> H₃₇Rv, <i>S. aureus</i> ATCC 25923, MRSA ATCC 43300, <i>Candida albicans</i> ATCC 10231, and their role in the inhibition of the biofilm formation of <i>S. aureus</i> were reported. 2-(5-Iodo-1<i>H</i>-indol-3-yl)quinazolin-4(3<i>H</i>)-one (<b>3k</b>) showed a low minimum inhibitory concentration (MIC) of 0.98 μg/mL against MRSA. The synthesized compounds were assessed via molecular docking for their ability to bind long RSH (RelA/SpoT homolog) proteins using mycobacterial and streptococcal (p)ppGpp synthetase structures as models. The cytotoxic activity of some synthesized compounds was studied. Compounds <b>3c</b>, <b>f</b>, <b>g</b>, <b>k</b>, <b>r</b>, and 3<b>z</b> displayed significant antiproliferative activities against all the cancer cell lines tested. Indolylquinazolinones <b>3b</b>, <b>3e</b>, and <b>3g</b> showed a preferential suppression of the growth of rapidly dividing A549 cells compared to slower growing fibroblasts of non-tumor etiology.