A decentralized solid compound storage facility managed by a centralized electronic platform at a growing drug discovery company.

Within a growing drug discovery company, scientists acquire (either through in house synthesis or purchase) then store, retrieve, and ship solid compound samples daily between multiple locations. The efficient management and tracking of this entire process to support drug discovery is a significant challenge. This article describes a decentralized and cost-effective inventory facility that simplifies the solid compound storage and retrieval process. Standardized storage cabinets from the market are utilized, providing a cost-effective physical infrastructure. The cabinets can be distributed across storage rooms at multiple sites and arranged into spaces with a variety of dimensions, allowing the system to be retrofitted into existing facilities and scaled up easily. We can provide storage close to work areas at each location, minimizing both unnecessary movement of staff and transportation of substances. We have applied a systematic barcoding method to the compound batch identifier that correlates with its compound location. This simplifies the compound registration process as well as the process of finding and returning compounds. Additionally, a centralized electronic platform has been employed to store, update and track solid compound information, such as properties, location and quantity. Compound shipment may be initiated from different sites, and a centralized electronic platform assists the information retrieval process, ensuring each location possesses up-to-date information. The electronic platform we present streamlines the management of compound registration, location tracking, weight updates and shipment information, facilitating seamless record sharing among all stakeholders. Every step of the process can be tracked in real time by the project team. The platform can be flexibly configured to adapt to an evolving set of storage locations, with all information and processes being audited.

In Vitro and In Vivo Efficacy of a Novel and Long-Acting Fungicidal Azole, PC1244, on Aspergillus fumigatus Infection.

The antifungal effects of the novel triazole PC1244, designed for topical or inhaled administration, against Aspergillus fumigatus were tested in a range of in vitro and in vivo studies. PC1244 demonstrated potent antifungal activities against clinical A. fumigatus isolates (n = 96) with a MIC range of 0.016 to 0.25 µg/ml, whereas the MIC range for voriconazole was 0.25 to 0.5 µg/ml. PC1244 was a strong tight-binding inhibitor of recombinant A. fumigatus CYP51A and CYP51B (sterol 14α-demethylase) enzymes and strongly inhibited ergosterol synthesis in A. fumigatus with a 50% inhibitory concentration of 8 nM. PC1244 was effective against a broad spectrum of pathogenic fungi (MIC range, <0.0078 to 2 µg/ml), especially Aspergillus terreus, Trichophyton rubrum, Candida albicans, Candida glabrata, Candida krusei, Cryptococcus gattii, Cryptococcus neoformans, and Rhizopus oryzae PC1244 also proved to be quickly absorbed into both A. fumigatus hyphae and bronchial epithelial cells, producing persistent antifungal effects. In addition, PC1244 showed fungicidal activity (minimum fungicidal concentration, 2 µg/ml) which indicated that it was 8-fold more potent than voriconazole. In vivo, once-daily intranasal administration of PC1244 (3.2 to 80 µg/ml) to temporarily neutropenic, immunocompromised mice 24 h after inoculation with itraconazole-susceptible A. fumigatus substantially reduced the fungal load in the lung, the galactomannan concentration in serum, and circulating inflammatory cytokine levels. Furthermore, 7 days of extended prophylaxis with PC1244 showed in vivo effects superior to those of 1 day of prophylactic treatment, suggesting accumulation of the effects of PC1244. Thus, PC1244 has the potential to be a novel therapy for the treatment of A. fumigatus infection in the lungs of humans.

In Vitro and In Vivo Antifungal Profile of a Novel and Long-Acting Inhaled Azole, PC945, on Aspergillus fumigatus Infection.

The profile of PC945, a novel triazole antifungal designed for administration via inhalation, was assessed in a range of in vitro and in vivo studies. PC945 was characterized as a potent, tightly binding inhibitor of Aspergillus fumigatus sterol 14α-demethylase (CYP51A and CYP51B) activity (50% inhibitory concentrations [IC50s], 0.23 µM and 0.22 µM, respectively) with characteristic type II azole binding spectra. Against 96 clinically isolated A. fumigatus strains, the MIC values of PC945 ranged from 0.032 to >8 µg/ml, while those of voriconazole ranged from 0.064 to 4 µg/ml. Spectrophotometric analysis of the effects of PC945 against itraconazole-susceptible and -resistant A. fumigatus growth yielded IC50 (determined based on optical density [OD]) values of 0.0012 to 0.034 µg/ml, whereas voriconazole (0.019 to >1 µg/ml) was less effective than PC945. PC945 was effective against a broad spectrum of pathogenic fungi (with MICs ranging from 0.0078 to 2 µg/ml), including Aspergillus terreus, Trichophyton rubrum, Candida albicans, Candida glabrata, Candida krusei, Cryptococcus gattii, Cryptococcus neoformans, and Rhizopus oryzae (1 or 2 isolates each). In addition, when A. fumigatus hyphae or human bronchial cells were treated with PC945 and then washed, PC945 was found to be absorbed quickly into both target and nontarget cells and to produce persistent antifungal effects. Among temporarily neutropenic immunocompromised mice infected with A. fumigatus intranasally, 50% of the animals survived until day 7 when treated intranasally with PC945 at 0.56 µg/mouse, while posaconazole showed similar effects (44%) at 14 µg/mouse. This profile affirms that topical treatment with PC945 should provide potent antifungal activity in the lung.

Point-to-helical chirality transfer for a scalable and resolution-free synthesis of a helicenoidal DMAP organocatalyst.

The synthesis of a second-generation [6]-helicenoidal DMAP organocatalyst is reported. The synthesis is reliant upon a highly diastereoselective Rh-catalysed [2 + 2 + 2] triyne cycloisomerization, using an existing stereocentre to control the sense of forming helicity. Taken together, a scalable (>1 g), resolution-free entry to a helical DMAP with the capacity for subsequent functionalization, has been achieved.

Design, synthesis, and evaluation of a helicenoidal DMAP Lewis base catalyst.

The design, synthesis, and study of a helical dialkylaminopyridine Lewis base catalyst is reported. Helical DMAP analogue 4 is based upon a helicenoid structure and displays good to excellent levels of selectivity (S ≤ 116) in the kinetic resolution of chiral secondary alcohols. Catalyst 4 displays excellent reactivity with exceptionally low loadings of 0.05 mol % effecting practical levels of selectivity in kinetic resolutions.

Abnormal coordination of Arduengo's carbene upon reaction with M(3)(CO)(12) (M = Ru, Os).

The first examples of abnormal coordination of Ardeungo's carbene, 1,3-bis-adamantylimidazol-2-ylidene, have been isolated and structurally characterised following reaction of the free carbene with the trinuclear clusters M(3)(CO)(12) (M = Ru, Os).