Commercial AHAS-inhibiting herbicides are promising drug leads for the treatment of human fungal pathogenic infections

The increased prevalence of drug-resistant human pathogenic fungal diseases poses a major threat to global human health. Thus, new drugs are urgently required to combat these infections. Here, we demonstrate that acetohydroxyacid synthase (AHAS), the first enzyme in the branched-chain amino acid biosynthesis pathway, is a promising new target for antifungal drug discovery. First, we show that several AHAS inhibitors developed as commercial herbicides are powerful accumulative inhibitors of Candida albicans AHAS (K-i values as low as 800 pM) and have determined high-resolution crystal structures of this enzyme in complex with several of these herbicides. In addition, we have demonstrated that chlorimuron ethyl (CE), a member of the sulfonylurea herbicide family, has potent antifungal activity against five different Candida species and Cryptococcus neoformans (with minimum inhibitory concentration, 50% values as low as 7 nM). Furthermore, in these assays, we have shown CE and itraconazole (a P450 inhibitor) can act synergistically to further improve potency. Finally, we show in Candida albicans-infected mice that CE is highly effective in clearing pathogenic fungal burden in the lungs, liver, and spleen, thus reducing overall mortality rates. Therefore, in view of their low toxicity to human cells, AHAS inhibitors represent a new class of antifungal drug candidates

Adamantane: the heavy weight in catalysis

The front cover image, provided by Kylie Agnew-Francis and Craig Williams, illustrates diverse examples of catalytic systems that contain the sterically bulky adamantane moiety. This 'big guy' molecule has become well regarded in the literature for its powerful electron-donating properties in addition to its size, and has thus marked its place in the organic chemist's toolbox as an excellent (and often superior) addition to catalyst and ligand design

Squaramides as bioisosteres in contemporary drug design

Squaramides represent a class of vinylogous amides that are derived from the squarate oxocarbon dianion. While they have been known since the 1950s, squaramides have only recently emerged (in the last 10-20 years) as particularly useful chemical entities in a variety of applications. They have found particular use as bioisosteric replacements of several heteroatomic functional groups, notably ureas, thioureas, guanidines, and cyanoguanidines, owing in part to their similar capacity toward hydrogen bonding and ability to reliably engender defined conformations in drug ligands. This Review aims to provide a comprehensive overview of the deployment of squaramides as bioisosteres within the drug design landscape. Their utility in this space is further rationalized through an examination of the physicochemical properties of squaramides in contrast to other functional groups. In addition, we consider the deployment of related cyclic oxocarbanion derivatives as potential bioisosteric replacements of ureas and related functional groups

Catalysts containing the adamantane scaffold

The bulky, but symmetrically beautiful, adamantane ring system is now pervasive throughout physical, medicinal and synthetic chemistry, since it was first discovered in 1924 and coined “dekaterpene”. This fascinating name lived up to its natural product roots when adamantane was isolated from crude oil in 1933, but it was not until 1957 in a landmark contribution by Paul von Ragué Schleyer that adamantane was made readily accessible through synthesis. Beyond the legacy to physical and medicinal chemistry, the adamantane moiety has been quintessential in the development of some of the most important catalysts to date. Considering adamantane’s impact on catalyst development past, present and future, this subject is for the first time reviewed herein

Humulene diepoxides from the Australian arid zone herb Dysphania: assignment of aged hops constituents

Dysphania is an abundant genus of plants, many of which are endemic to the Australian continent, occurring primarily in arid and temperate zones. Despite their prevalence, very few investigations into the phytochemistry of native Dysphania have been undertaken. Described herein, is the isolation and elucidation of two enantiomeric diastereomers of humulene diepoxide C from D. kalpari and D. rhadinostachya, of which unassigned diastereomers of humulene diepoxide C have been previously reported as components in beer brewed from aged hops. In addition, two (+)-humulene diepoxiols (humulene diepoxiol C-I and C-II) were isolated from D. rhadinostachya. Analysis of Chinook hops oil confirmed the presence of both humulene diepoxide C-I and C-II as trace components, and in turn enabled GC-MS peak assignment to the relative stereochemistry. Anticancer assays did not reveal any significant activity for the (+)-humulene diepoxides. Antifungal assays showed good activity against a drug-resistant strain of C. auris, with MIC values of 8.53 and 4.91 μm obtained for (+)-humulene diepoxide C-I and C-II, respectively

Herbicides that target acetohydroxyacid synthase are potent inhibitors of the growth of drug resistant Candida auris

Acetohydroxyacid synthase (AHAS, EC 2.2.1.6) is the first enzyme in the branched chain amino acid biosynthesis pathway, is the target for more than 50 commercially available herbicides and is a promising target for antimicrobial drug discovery. Herein, we have expressed and purified AHAS from Candida auris, a newly identified human invasive fungal pathogen. Ten AHAS inhibiting herbicides have Ki values of 100 M and thus possesses a therapeutic index of >100. These data suggest that targeting AHAS is a viable strategy for treating C. auris infections