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As the rate of discovery of new antibacterial compounds for multidrug-resistant bacteria is declining, there is an urge for the search for molecules that could revert this tendency. <i>Acinetobacter baumannii</i> has emerged as a highly virulent Gram-negative bacterium that has acquired multiple resistance mechanisms against antibiotics and is considered of critical priority. In this work, we developed a quantitative structure-property relationship (QSPR) model with 592 compounds for the identification of structural parameters related to their property as antibacterial agents against <i>A. baumannii</i>. QSPR mathematical validation (<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><msup><mi>R</mi><mn>2</mn></msup></mrow></semantics></math></inline-formula> = 70.27, <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><msup><mi>R</mi><mi>N</mi></msup><mo> </mo></mrow></semantics></math></inline-formula>= −0.008, <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><mi>a</mi><mrow><mo>(</mo><mrow><msup><mi>R</mi><mn>2</mn></msup></mrow><mo>)</mo></mrow><mo> </mo></mrow></semantics></math></inline-formula>= 0.014, and <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><mi>δ</mi><mi>K</mi></mrow></semantics></math></inline-formula> = 0.021) and its prediction ability (<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><msup><mi>Q</mi><mn>2</mn></msup></mrow></semantics></math></inline-formula><i>_LMO</i>= 67.89, <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><msup><mi>Q</mi><mn>2</mn></msup></mrow></semantics></math></inline-formula><i>_EXT</i> = 67.75, <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><mi>a</mi><mrow><mo>(</mo><mrow><msup><mi>Q</mi><mn>2</mn></msup></mrow><mo>)</mo></mrow></mrow></semantics></math></inline-formula> = −0.068, <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><mi>δ</mi><mi>Q</mi></mrow></semantics></math></inline-formula> = 0.0, <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><mover accent="true"><mrow><msub><mi>r</mi><mi>m</mi></msub><msup><mrow></mrow><mn>2</mn></msup></mrow><mo stretchy="true">¯</mo></mover></mrow></semantics></math></inline-formula> = 0.229, and <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><mo>Δ</mo><msub><mi>r</mi><mi>m</mi></msub><msup><mrow></mrow><mn>2</mn></msup></mrow></semantics></math></inline-formula> = 0.522) were obtained with different statistical parameters; additional validation was done using three sets of external molecules (<inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mrow><msup><mi>R</mi><mn>2</mn></msup></mrow></semantics></math></inline-formula> = 72.89, 71.64 and 71.56). We used the QSPR model to perform a virtual screening on the BIOFACQUIM natural product database. From this screening, our model showed that molecules <b>32</b> to <b>35</b> and <b>54</b> to <b>68</b>, isolated from different extracts of plants of the <i>Ipomoea</i> sp., are potential antibacterials against <i>A. baumannii</i>. Furthermore, biological assays showed that molecules <b>56</b> and <b>60</b> to <b>64</b> have a wide antibacterial activity against clinically isolated strains of <i>A. baumannii</i>, as well as other multidrug-resistant bacteria, including <i>Staphylococcus aureus</i>, <i>Escherichia coli</i>, <i>Klebsiella pneumonia</i>, and <i>Pseudomonas aeruginosa</i>. Finally, we propose <b>60</b> as a potential lead compound due to its broad-spectrum activity and its structural simplicity. Therefore, our QSPR model can be used as a tool for the investigation and search for new antibacterial compounds against <i>A. baumannii</i>.