Abstract
A new class of potential antibacterial agents has been synthesized on a new molecular scaffold of cyclohexane carboxylate. We have tagged this new class of compounds TACCs (Trisubstituted Aryl Cyclohexanecarboxylate). These new molecules are structural analogues of an Activators of Self-Compartmentalizing Proteases 4 and 5 (ACP 4 and 5), and were synthesized to circumvent the drug-like property (drug-ability) challenges and liability noted in ACP 4 and 5. A pseudo-Robinson annulation protocol was used to furnish this new class of potential antibiotics. Structure-activity relationship (SAR) study was done to identify the pharmacophore(s) in this molecular scaffold. A selection of these compounds was used in our preliminary antibacterial inhibitory activities’ studies on Bacillus mycoides and Bacillus subtilis. These preliminary studies show that the TACCs exhibited equal, and in some cases better, antibacterial activity than ACP 4 and 5.
Highlights
A tremendous increase in the worldwide spread of antibiotic-resistant bacteria has spurred a lot of interests in the search for antibiotics with new modes of action
These new molecules are structural analogues of an Activators of Self-Compartmentalizing Proteases 4 and 5 (ACP 4 and 5), and were synthesized to circumvent the drug-like property challenges and liability noted in Activator of Cylindrical Proteases (ACP) 4 and 5
A new class of antibacterial agents has been synthesized on a new molecular scaffold of cyclohexane carboxylate
Summary
A tremendous increase in the worldwide spread of antibiotic-resistant bacteria has spurred a lot of interests in the search for antibiotics with new modes of action. Cellular pathways that are paramount to the survival of the bacterium at the early stages of the infection process have been identified as attractive candidates for rational drug design [4] In these endeavors, Clp protease, which is one of the major cellular proteases responsible for degrading misfolded or damaged proteins and plays an essential role in maintaining protein function, has been established as a suitable target for new antibiotics [4]-[11]. The investigations of the crystal structures of ClpP from different species, including bacterial, human, plants and yeast [20], have revealed that the protease is highly conserved [9] [21] [22] [23] These crystal structures show that ClpP assembles into a tetradecameric barrel-shaped enzyme having an enclosed chamber that contains 14 serine proteolytic active sites [22]. Its inhibition by cyclic peptides [25], β-lactones [17] [26] [27] [28] [29], and its acti-
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