## 7 Conclusions and Future Directions for Viniferins and Viniferin-Based Derivatives  
Previous research aiming at viniferins, their semi-synthetic as well as synthetic analogues and derivatives proved that they represented an extraordinarily promising class of compounds capable of fighting in vitro very efficiently several Gram-positive bacterial strains. This knowledge was extremely important in the overall context of the effective treatment of infections caused by these pathogens. However, the path of a compound that shows promising pharmacological activity for a prospective drug candidate, or even a drug approved for clinical use, is rather complicated and not always straightforward. The fundamental step in the process of drug design and development is to characterize such a biologically prospective molecule very comprehensively with respect to its PD, selectivity, structural, physicochemical, PK, and toxicological properties. The indisputable advantage of the presently investigated viniferins and viniferin-based compounds was the presence of two types of privileged structures, i.e., a benzo[\(b\)]furan or 2,3-dihydroenzo[\(b\)]furan core, which formed their fundamental structural framework. The arrangement gave hope that a desired type of pharmacological activity could be achieved and eventually utilized in the future to improve human health. The intention of a current review paper was to advance the knowledge in the field of antibacterial very active viniferins and their derivatives with respect to further phases of their development and optimization. The presently employed in silico methods provided at least a primary view on the structural, physicochemical, PK, and even toxicological characteristics of these compounds to tentatively indicate their developability and drug-likeness. The proposed structural modifications of naturally occurring viniferins (**16**)-**(21)** led to the synthesis of the compounds (**22**)-**(29)** with relatively improved antibacterial efficiency. These changes were reflected in the decreased _NP score_ index, informing about a measure by which these structurally modified compounds were still NPs (Table S7). In this regard, 5-[[3-(3,5-dihydroxyphenyl)-2-(4-hydroxyphenyl)]benzofuran-5-yl]phenyl]benzene-1,3-diol (**23**) was that with the lowest 'natural character'. The _QED_ parameter [135,136] indicated the probability that an analyzed compound can be a therapeutic agent. The calculated _QED_ value of 0.436 was related to (_E_)-2-(4-hydroxyphenyl)-4-(4-hydroxyyryl)benzofuran-6-ol (**29**) and the output was the highest among the _QED_s generated for the entire (**16**)-**(29)** set. However, halogenated compounds (**25**)-**(27)** were computationally considered to have the most promising potential to be convenient structural platforms that could be utilized in drug design and development following another calculated criterion, the _MCE-18_ descriptor (Table S7). In fact, their _MCE-18_s ranged from 90.412 (both (**25**) and (**26**)) to 93.529 (**27**), reliably exceeding the threshold _MCE-18_ value of \(\geq\) 45.00. Paradoxically, the perspectives of the compound (**29**) were the lowest in this regard. These observations could also be visualized globally using the PCA technique (Figure 16). All investigated compounds were distributed in four different areas following their properties within the constructed PC 1 \(\times\) PC 2 coordinate system. The areas were indicated with one ring and three ellipses. The derivatives were properly defined with positive or negative PCs. These PCs accounted for 66.39% of the total variance in the data as follows: PC 1 (42.10%, \(\lambda_{\rm e}=19.37\)) and PC 2 (24.29%, \(\lambda_{\rm e}=11.17\)). The details about this PCA, including the palette of the descriptors aimed at the given evaluation, are provided in Supplementary Materials. Focusing especially on the most prospective derivatives, the compound **(29)** was'slightly isolated' on the left, and described with negative PC 1 and positive PC 2.