γ-amino butyric acid (GABA) is an inhibitory neurotransmitter whose deficiency has been associated with various neurological disorders. However, its low liposolubility limits its use as a supplement. Thus, multiple investigations have focused on searching for lipophilic GABA analogs that can modulate the activity of the GABA_B receptor, which could be associated with the etiology of some central nervous system disorders. The GABA analogs available on the market are Vigabatrin, Gabapentin as well as Pregabalin and Baclofen. In this work, we report on the synthesis of GABA analogs, taking the scaffold of GABA, Pregabalin, and Baclofen as a starting point. The analogs include structural features that could favor the affinity of the molecules for the GABA_B receptor, such as heterocyclic rings in the γ-position and alkyl or p-Cl-phenyl substituents (in analogy to Pregabalin and Baclofen, respectively). These analogs were synthesized by a sequence of reactions involving an N-alkylation, a 1,4-conjugated addition of dialkyl and diarylcuprates and a basic hydrolysis. Furthermore, a computational molecular docking over the GABA_B receptor was performed to evaluate the interaction of each compound in the Baclofen binding site. With this information, we evaluated our compounds as GABA_B agonists through a QSAR analysis. Finally, by means of molecular similarity analysis, and in silico ADME prediction, we support our three best compounds (8a–b, 8d) as potential GABA_B receptor agonists.

Staphylococcus aureus (S. aureus) remains a major global pathogen and a significant public health concern due to its antibiotic resistance. This has spurred the search for new treatments, resulting in the discovery of two promising targets: FtsZ and FabI. Naturally occurring compounds berberine and lipophilic acids are known to bind these enzymes, respectively. This study aims to improve berberine’s binding affinity for FtsZ and enhance its interaction with FabI by designing hybrid compounds that could serve as dual inhibitors, targeting both active and allosteric sites. Forty-eight hybrids, derived from berberine and lipophilic acids with 10 to 22 carbons, were modeled. Molecular docking against five S. aureus enzyme crystal structures identified six compounds with geranic acid chains (1s, 1t, 1u, 2s, 2t, 2u) that showed the strongest binding. Among these, 2s, 2t, and 1t showed the greatest affinity for FtsZ, while 2u, 1u, and 1s targeted FabI, with binding energies around −8.2 to −10.5 kcal/mol. QSAR models estimated MICs within known inhibitor ranges, implying potential effectiveness. Hydrophobic and flexible features correlated with stronger interactions and activity. ADMET analysis indicated low toxicity for these hybrids. Modifying berberine with lipophilic acids appears to be a promising approach for developing plant-based dual inhibitors against S. aureus.