Current drugs for treating human cytomegalovirus (HCMV) infections are limited by resistance and treatment-associated toxicities. In developing mechanistically novel HCMV antivirals, we discovered an N-benzyl hydroxypyridone carboxamide antiviral hit (8a) inhibiting HCMV in submicromolar range. We describe herein the structure-activity relationship (SAR) for 8a, and the characterization of potent analogs for cytotoxicity/cytostatic property, the preliminary mechanism of action, and the absorption, distribution, metabolism and excretion (ADME) properties. The SAR revealed a few pharmacophore features conferring optimal antiviral profile, including the 5-OH, the N-1 benzyl, at least one -CH2- in the linker, and a di-halogen substituted phenyl ring in the amide moiety. In the end, we identified numerous analogs with sub-micromolar antiviral potency and good selectivity index. The preliminary mechanism of action characterization used a pUL89-C biochemical endonuclease assay, a virus entry assay, a time-of-addition assay, and a compound withdrawal assay. ADME profiling measuring aqueous solubility, plasma and liver microsomal stability, and parallel artificial membrane permeability assay (PAMPA) permeability demonstrated largely favorable drug-like properties. Together, these studies validate the N-benzyl hydroxypyridone carboxamide as a viable chemotype for potent and mechanistically distinct antivirals against HCMV.

Within the framework of discovery chemistry, polyfluorination remains a synthetic challenge despite its ability to provide useful characteristics, such as a reduction in the number of hydrogen bond donors and metabolic stability. Coupling a reversal of this methodology with photocatalysis has been demonstrated to allow the rapid synthesis of previously difficult or impossible targets by starting with fluorines everywhere and selectively removing or functionalizing them. Herein, we demonstrate a novel method to synthesize 1,4-cyclohexadienes through a dearomative photocatalytic C-C coupling reaction. This allows for access to materials that are orthogonal to the selectivity of the Birch reaction and are more functional-group-tolerant. The reaction also allows the efficient synthesis of polyfluorinated cannabinoids. While the yields are modest, the access to the new chemical space provided by the reaction is unprecedented by any means. The trifluorinated analog of THC, 1-deoxy-1,2,4-trifluoro-THC, is synthesized, demonstrating the importance of discovery chemistry and the ability to explore otherwise unknown structure-activity relationships.

Hepatitis B virus (HBV) capsid assembly modulators (CpAMs) have shown promise as potent anti-HBV agents in both preclinical and clinical studies. Herein, we report our efforts in identifying novel CpAM hits via a structure-based virtual screening against a small molecule protein-protein interaction (PPI) library, and pharmacophore-guided compound design and synthesis. Curated compounds were first assessed in a thermal shift assay (TSA), and the TSA hits were further evaluated in an antiviral assay. These efforts led to the discovery of two structurally distinct scaffolds, ZW-1841 and ZW-1847, as novel HBV CpAM hits, both inhibiting HBV in single-digit µM concentrations without cytotoxicity at 100 µM. In ADME assays, both hits displayed extraordinary plasma and microsomal stability. Molecular modeling suggests that these hits bind to the Cp dimer interfaces in a mode well aligned with known CpAMs.

Tyrosyl-DNA phosphodiesterase 2 (TDP2) repairs topoisomerase II (Top2) mediated DNA damages, including double-strand breaks (DSBs) that underpin the anticancer mechanism of clinical TOP2 poisons such as etoposide (ETP). Inhibition of TDP2 could sensitize cancer cells toward TOP2 poisons by increasing Top2 cleavage complex. We have previously identified isoquinoline-1,3-dione as a selective inhibitor type of TDP2. However, the reported structure-activity relationship (SAR) was limited to simple substitutions on the isoquinoline-1,3-dione core. Herein, we report the extended SAR consisting of the synthesis and testing of a total of 50 analogs featuring N-2 and C-4 modifications. Major SAR observations include the loss of potency upon N-2 substitution, the lack of inhibition with C-4 enamine analogs (subtype 11), or any other C-4 modifications (subtypes 13-15) except for the benzylidene substitution (subtype 12), where eight analogs showed low micromolar potency. The best analog, 12q, inhibited TDP2 with an IC50 of 4.8 μM. Molecular modeling was performed to help understand the observed SAR trends. Overall, these SAR observations which could significantly benefit future work on the design of improved TDP2 inhibitors.

Organic molecules bearing acetoxy moieties are important functionalities in natural products, drugs, and agricultural chemicals. Synthesis of such molecules via transition metal-catalyzed C-O bond formation can be achieved in the presence of a carefully chosen directing group to alleviate the challenges associated with regioselectivity. An alternative approach is to use ubiquitous carboxylic acids as starting materials and perform a decarboxylative coupling. Herein, we report conditions for a photocatalytic decarboxylative C-O bond formation reaction that provides rapid and facile access to the corresponding acetoxylated products. Mechanistic investigations suggest that the reaction operates via oxidation of the carboxylate followed by rapid decarboxylation and oxidation by Cu(OAc)(2).

Selective catalytic SNAr reaction of polyfluoroaryl C-F bonds with chloride is shown. Stoichiometric TMSCl makes the reaction exergonic and allows catalysis, which involves ground state elevation of chloride, aromatic donor-acceptor interactions, and stabilization of the Meisenheimer complex. Traditional cross-coupling of the products is now possible and demonstrates the utility.

Multifluorinated biaryls are challenging to synthesize and yet are an important class of molecules. Because of the difficulty associated with selective fluorination, this class of molecules represent a formidable synthetic challenge. An alternative approach to selective fluorination of biaryls is to couple an arene that already possesses C-F bonds in the desired location. This strategy has been regularly utilized and relies heavily on traditional cross-coupling strategies that employ organometallics and halides (or pseudohalides) in order to achieve the coupling. Herein we report conditions for the photocatalytic coupling via direct functionalization of the C-F bond of a perfluoroarene and C-H bond of the other arene to provide an expedient route to multifluorinated biaryls. The mild conditions and good functional group tolerance enable a broad scope, including access to the anti-Minisci product of basic heterocycles. Finally, we demonstrate the value of the C-F functionalization approach by utilizing the high fluorine content to systematically build complex biaryls containing between two and five Caryl-F bonds via the synergistic use of photocatalysis and SNAr chemistry.

Functionalized polyfluorinated aromatics have become an important group of molecules for pharmaceutical and industrial applications. However, facile access to such valuable molecules remains an unmet challenge. In this review, we present and discuss photocatalytic C-F functionalization, which is emerging as a straightforward and operationally simple path to access partially fluorinated aromatics.

This photocatalytic coupling of one C—F bond of a polyfluoroarene with the C—H bond of another arene uses readily accessible starting materials, proceeds under mild conditions, and shows high functional group tolerance, thus offering a benign alternative to traditional cross-coupling strategies.

ChemInformVolume 46, Issue 17 Preparative Organic Chemistry ChemInform Abstract: Selective Perfluoro- and Polyfluoroarylation of Meldrum′s Acid. Sameera M. Senaweera, Sameera M. Senaweera Dep. Chem., Okla. State Univ., Stillwater, OK 74078, USASearch for more papers by this authorJimmie D. Weaver, Jimmie D. Weaver Dep. Chem., Okla. State Univ., Stillwater, OK 74078, USASearch for more papers by this author Sameera M. Senaweera, Sameera M. Senaweera Dep. Chem., Okla. State Univ., Stillwater, OK 74078, USASearch for more papers by this authorJimmie D. Weaver, Jimmie D. Weaver Dep. Chem., Okla. State Univ., Stillwater, OK 74078, USASearch for more papers by this author First published: 09 April 2015 https://doi.org/10.1002/chin.201517053Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume46, Issue17April, 2015 RelatedInformation

Polyfluorinated aromatics are essential to materials science as well as the pharmaceutical and agrochemical industries and yet are often difficult to access. This Communication describes a photocatalytic hydrodefluorination approach which begins with easily accessible perfluoroarenes and selectively reduces the C-F bonds. The method allows facile access to a number of partially fluorinated arenes and takes place with unprecedented catalytic activity using a safe and inexpensive amine as the reductant.