Divergent synthesis of a thiolate-based α-hydroxytropolone library with a dynamic bioactivity profile

Agyemang, Nana B.; Kukla, Cassandra R.; Edwards, Tiffany C.; Li, Qilan; Langen, Madison K; Schaal, Alexandra; Franson, Abaigeal D.; Casals, Andreu Gazquez; Donald, Katherine A.; Yu, Alice J.; Donlin, Maureen J.; Morrison, Lynda A.; Tavis, John E.; Murelli, Ryan P.

doi:10.1039/c9ra06383h

Cited by 11 publications

(6 citation statements)

References 42 publications

(21 reference statements)

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“…Intriguingly, both acylated thiotropolones (680, 686) had sub-mM activity despite the lack of any tridentate cation binding motif. It seems possible that these thioester linkages could undergo cleavage in the cell, and that the active component in both instances is the free thiotropolone, as has been postulated previously for their potent anti-Cryptococcus neoformans activity [37].…”

Section: Plos Onementioning

confidence: 64%

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Metal coordinating inhibitors of Rift Valley fever virus replication

et al. 2022

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Rift Valley fever virus (RVFV) is a veterinary and human pathogen and is an agent of bioterrorism concern. Currently, RVFV treatment is limited to supportive care, so new drugs to control RVFV infection are urgently needed. RVFV is a member of the order Bunyavirales, whose replication depends on the enzymatic activity of the viral L protein. Screening for RVFV inhibitors among compounds with divalent cation-coordinating motifs similar to known viral nuclease inhibitors identified 47 novel RVFV inhibitors with selective indexes from 1.1-103 and 50% effective concentrations of 1.2-56 μM in Vero cells, primarily α-Hydroxytropolones and N-Hydroxypyridinediones. Inhibitor activity and selective index was validated in the human cell line A549. To evaluate specificity, select compounds were tested against a second Bunyavirus, La Crosse Virus (LACV), and the flavivirus Zika (ZIKV). These data indicate that the α-Hydroxytropolone and N-Hydroxypyridinedione chemotypes should be investigated in the future to determine their mechanism(s) of action allowing further development as therapeutics for RVFV and LACV, and these chemotypes should be evaluated for activity against related pathogens, including Hantaan virus, severe fever with thrombocytopenia syndrome virus, Crimean-Congo hemorrhagic fever virus.

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Section: Plos Onementioning

confidence: 64%

“…For 169 and 362 see [36]. For 385, 694, 696, 698, 700, 702, 704, 703, 838, and 840 see [37]. For 321, 336, 358, and 359 see [38].…”

Section: Compound Acquisition and Synthesismentioning

confidence: 99%

Metal coordinating inhibitors of Rift Valley fever virus replication

et al. 2022

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“…For 169 and 362 see [24]. For 385, 694, 696, 698, 700, 702, 704, 703, 838, and 840 see [25]. For 321, 336, 358, and 359 see [26].…”

Section: Compound Acquisition and Synthesismentioning

confidence: 99%

Metal Coordinating Inhibitors of Rift Valley Fever virus Replication

Geerling

Murphy

Stone

et al. 2022

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Rift Valley Fever Virus (RVFV) is a veterinary and human pathogen and is an agent of bioterrorism concern. Currently, RVFV treatment is limited to supportive care, so new drugs to control RVFV infection are urgently needed. RVFV is a member of the Bunyavirales order, and replication of these viruses depends on the viral endonuclease activity of the viral L protein. Screening for RVFV replication inhibitors among compounds with divalent cation-coordinating motifs similar to known viral nuclease inhibitors identified 31 novel RVFV inhibitors with selective indexes from 5 – 402 and 50% effective concentrations of 0.54 – 56 µM in Vero cells, primarily α-Hydroxytropolones and N-Hydroxypyridinediones. Inhibitor activity and selective index was validated in the human cell line A549. To evaluate specificity, select compounds were tested against another Bunyavirus, La Crosse Virus (LACV). Conservation of the enzymatic activity such as the cap-snatching mechanism among the Bunyavirales implies that the α-Hydroxytropolone and N-Hydroxypyridinedione chemotypes hold potential for development into treatments for related pathogens, including Hantaan Virus, Severe fever with thrombocytopenia syndrome virus, Crimean-Congo Hemorrhagic Fever Virus, and LACV. Keywords: Rift Valley Fever Virus 1, La Crosse virus 2, Cap-snatching endonuclease 3, Replication inhibitors 4, α-Hydroxytropolones 5, N-Hydroxypyridinediones 6.

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“…Further structure-activity relationship studies on the hydroxylated tropolone ring revealed that the α-OH substitution is essential for the HBV RNaseH inhibition. Bulky substitution in positions R 1 , R 2 and R 3 leads to a decreased inhibitory activity, indicating that sulfonyl- or lactone substituents can increase the efficacy [ 190 , 191 , 193 ]. These findings have been validated by recent studies, which also highlighted the increased efficacy of amide-substituted α-HTs [ 194 , 195 , 196 ].…”

Section: Novel Therapeutic Strategiesmentioning

confidence: 99%

Recent Advances in Hepatitis B Treatment

et al. 2021

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Hepatitis B virus infection affects over 250 million chronic carriers, causing more than 800,000 deaths annually, although a safe and effective vaccine is available. Currently used antiviral agents, pegylated interferon and nucleos(t)ide analogues, have major drawbacks and fail to completely eradicate the virus from infected cells. Thus, achieving a “functional cure” of the infection remains a real challenge. Recent findings concerning the viral replication cycle have led to development of novel therapeutic approaches including viral entry inhibitors, epigenetic control of cccDNA, immune modulators, RNA interference techniques, ribonuclease H inhibitors, and capsid assembly modulators. Promising preclinical results have been obtained, and the leading molecules under development have entered clinical evaluation. This review summarizes the key steps of the HBV life cycle, examines the currently approved anti-HBV drugs, and analyzes novel HBV treatment regimens.

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Divergent synthesis of a thiolate-based α-hydroxytropolone library with a dynamic bioactivity profile

Abstract: A library of α-hydroxytropolones synthesized through a simple halogenation/thiolate addition sequence reveals molecules with potent activity against three human pathogens.

Cited by 11 publications

References 42 publications

Metal coordinating inhibitors of Rift Valley fever virus replication

Metal coordinating inhibitors of Rift Valley fever virus replication

Metal Coordinating Inhibitors of Rift Valley Fever virus Replication

Recent Advances in Hepatitis B Treatment

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