Mild Method for Deprotection of the N-Benzyloxycarbonyl (N-Cbz) Group by the Combination of AlCl3 and HFIP.

Herein, we report our findings on the novel ability of aluminum chloride (AlCl3) in fluorinated solvent 1,1,1,3,3,3-hexafluoroisopropanol [HFIP] to selectively deprotect the N-benzyloxycarbonyl group (N-Cbz). The salient features of this method are good functional group tolerance including other reducible groups, cost-effectiveness, easy-to-handle, safe protocol, amenable to scale-up, high yields, and ambient temperature reactions. The methodology would serve as an excellent alternative to the use of pyrophoric hydrogen gas and metal catalyst reagents that pose severe safety and environmental concerns. The most notable feature of this methodology is the orthogonal deprotection of the N-Cbz group in the presence of O- and N-Bn protecting groups, hence, expanding the scope for designing synthetic routes to target compounds requiring multiple functional group transformations.

TBAT-Catalyzed Deoxygenative Reduction of Tertiary Amides to Amines.

A simple, mild, metal-free catalytic protocol is developed to convert amides to amines. This protocol uses a stable tetrabutylammonium difluorotriphenylsilicate in combination with silanes that generates a highly reactive hydrosilicate species, which enables the reduction of a broad range of amides to amines in moderate to good yields. The attractive features of this protocol include operational simplicity, safety, short reaction times, room temperature reaction, broad substrate scope, and amenable to scale up.

Visible-Light-Promoted Dual Photoredox/Nickel-Catalyzed Chemoselective Reduction of Secondary and Tertiary Amides with Hydrosilanes in the Presence of an Ester.

We report a one-step procedure to selectively reduce secondary and tert-amides to their corresponding amine derivatives in the presence of an ester. This was achieved via the synergistic combination of a photoredox, a nickel catalytic system, and phenyl silane as a reductant in the presence of blue light-emitting diode light (455 nm) at room temperature. Further, this mild light-promoted dual metallaphotoredox catalytic system was also successful in selectively reducing a lactam to the cyclic amines, without affecting the ester moiety present in the molecules.

AlCl3-Mediated CHF2 Transfer and Cyclocondensation of Difluoromethoxy Functionalized o-Phenylenediamines to Access N-Substituted Benzimidazoles.

Herein, we report for the first time a transition-metal-free frustrated Lewis pair (FLP) catalyzed CHF2 group migration from an oxygen atom to the neighboring nitrogen atom, which led to the synthesis of N-substituted benzimidazoles at room temperature with excellent yields, broad functional group tolerance, and a short reaction time. The oxygen-attached difluoromethane acted as a C1 source in the synthesis of N-substituted benzimidazoles in the presence of AlCl3 by cleaving one C-O bond and two C-F bonds, resulting in formation of two new C-N bonds.

Synthetic derivatives of the antifungal drug ciclopirox are active against herpes simplex virus 2.

We previously showed that the anti-fungal drug ciclopirox olamine effectively inhibits replication of herpes simplex virus (HSV)-1 and HSV-2. Given the rise of HSV strains that are resistant to nucleos(t)ide analog treatment, as well as the incomplete efficacy of nucleos(t)ide analogs, new inhibitory compounds must be explored for potential use in the treatment of HSV infection. In the present study, we analyzed 44 compounds derived from the core structure of ciclopirox olamine for inhibitory activity against HSV. Thirteen of these derivative compounds inhibited HSV-2 replication by > 1000- to ∼100,000-fold at 1 µM and displayed EC50 values lower than that of acyclovir, as well as low cytotoxicity, indicating their strong therapeutic potential. Through structural comparison, we also provide evidence for the importance of various structural motifs to the efficacy of ciclopirox and its derivatives, namely hydrophobic groups at R4 and R6 of the ciclopirox core structure. Like ciclopirox, representative analogs exhibit some oral bioavailability but are rapidly cleared in vivo. Together, these results will guide further development of N-hydroxypyridones as HSV therapeutics.

Synthetic Derivatives of Ciclopirox are Effective Inhibitors of Cryptococcus neoformans.

Opportunistic fungal infections caused by Cryptococcus neoformans are a significant source of mortality in immunocompromised patients. They are challenging to treat because of a limited number of antifungal drugs, and novel and more effective anticryptococcal therapies are needed. Ciclopirox olamine, a N-hydroxypyridone, has been in use as an approved therapeutic agent for the treatment of topical fungal infections for more than two decades. It is a fungicide, with broad activity across multiple fungal species. We synthesized 10 N-hydroxypyridone derivatives to develop an initial structure-activity understanding relative to efficacy as a starting point for the development of systemic antifungals. We screened the derivatives for antifungal activity against C. neoformans and Cryptococcus gattii and counter-screened for specificity in Candida albicans and two Malassezia species. Eight of the ten show inhibition at 1-3 µM concentration (0.17-0.42 µg per mL) in both Cryptococcus species and in C. albicans, but poor activity in the Malassezia species. In C. neoformans, the N-hydroxypyridones are fungicides, are not antagonistic with either fluconazole or amphotericin B, and are synergistic with multiple inhibitors of the mitochondrial electron transport chain. They appear to function primarily by chelating iron within the active site of iron-dependent enzymes. This preliminary structure-activity relationship points to the need for a lipophilic functional group at position six of the N-hydroxypyridone ring and identifies positions four and six as sites where further substitution may be tolerated. These molecules provide a clear starting point for future optimization for efficacy and target identification.

Evaluation of 2-thioxo-2,3,5,6,7,8-hexahydropyrimido[4,5-d]pyrimidin-4(1H)-one analogues as GAA activators.

Pompe disease is a lysosomal storage disease (LSD) caused by a deficiency in the lysosomal enzyme acid alpha-glucosidase. In several LSDs, enzyme inhibitors have been used as small molecule chaperones to facilitate and increase the translocation of mutant protein from the endoplasmic reticulum to the lysosome. Enzyme activators with chaperone activity would be even more desirable as they would not inhibit the enzyme after translocation and might potentiate the activity of the enzyme that is successfully translocated. Herein we report our initial findings of a new series of acid alpha-glucosidase activators.