Webster L. Santos

Invasive fungal infections are a major and escalating global health concern, frequently resulting in life-threatening systemic infection. The combination of limited therapeutic options, increasing mortality, and the rapid emergence of multidrug-resistant fungal pathogens highlights the critical need for novel antifungal agents. With this goal in mind, a high-throughput screening assay identified SLB1122168, and a subsequent structure−activity relationship study led to more potent analogs, including SSD2032594, which demonstrated fungicidal activity with a minimum inhibitory concentration of 1−4 μg/mL against Candida auris, Cryptococcus neoformans, Aspergillus fumigatus, and Mucormycosis-causing species. Additionally, SSD2032594 showed potent activity against mature biofilms of C. auris and exhibited a negligible resistance tendency in vitro. Furthermore, SSD2032594 showed a survival benefit in the Caenorhabditis elegans nematode model of C. auris infection, resulting in a ∼30% higher survival rate. Taken together, these results highlight SSD2032594 as a candidate for antifungal drug development, targeting infections caused by different fungal pathogens.

We report a mild synthesis of 1,2,4-oxadiazoles via the dipolar cycloaddition of N-hydroxybenzimidoyl chlorides with nitriles under metal-free and catalyst-free conditions. We demonstrate a wide-substrate scope with aryl, heteroaryl, and alkyl substituents on both substrates with yields up to 91%.

Accessing complex α,β-dehydroamino acids remains challenging due to the instability of the enamine product during N-terminal deprotection. We report a mild, organocatalytic method for the installation of primary amides on the α-carbon of alkynoates that avoids N-terminal deprotection. The PBu3 catalyst is key to umpolung reactivity and affords α,β-dehydroamino acids in good yield with excellent (Z)-selectivity. The utility of this reaction was demonstrated in the synthesis of two natural products: a 2,5-diketopiperazine and scutianene M.

The mechanistic details of the chemo‐, regio‐, and stereoselective cis ‐hydroboration of 1,3‐enynes were investigated using X‐ray crystallography, kinetic analysis, and density functional theory (DFT) calculations. The kinetic analysis revealed that the reaction is first order in enyne, zeroth order in HBpin, and fractional order in the catalyst. Our studies suggest that a cyclic CuHBpinOAc complex is an off‐cycle species (via DFT analysis) that contributes to the experimentally observed fractional rate order regarding the catalyst. Experimental and computational data suggest that hydrocupration is rate‐limiting and essential for achieving selectivity.

Antimicrobial resistance is an imminent health threat worldwide. Development of alternative treatments for drug-resistant microbes is of paramount importance. Targeting virulence factors, such as the type IV pilus construction enzyme PilB, is a strategy of treatment. Recently, we reported the discovery of a potent inhibitor of PilB, the FDA approved drug benserazide (IC₅₀ = 3.68 μM). Herein, we report the structure–activity relationship profiling of benserazide analogues and identify key moieties that enable PilB inhibition. We found that bis-hydroxyl groups on the ortho position of the aryl ring, a rigid imine, and exchange of the serine for a thiol have resulted in marked improvement in potency. Our studies identified 11c as a PilB inhibitor with an IC₅₀ of 580 nM and selectivity for PilB over an unrelated ATPase, apyrase. These compounds provide the chemical tools to validate virulence factors as antibacterial mechanisms of action.