Accessing Rare Heterocycles from Alkynyl Ethers and Nitrogenous Electrophiles & The Development of Small Molecule Inhibitors Against Naegleria \u3ci\u3efowleri\u3c/i\u3e infection

https://tigerprints.clemson.edu/csrp/1002/thumbnail.jp

α-D-glucopyranosyl-(1→2)-[6-O-(L-tryptophanyl)-β-D-fructofuranoside]

Funding: K.K. wishes to thank the Centre for African Wetlands (CAW), University of Ghana, for providing seed funding to enable the collection of soil samples for microbe isolation and a TWAS Research Grant Award_17-512 RG/CHE/AF/AC_G. K.K. is also very grateful to the Cambridge-Africa Partnership for Research Excellence (CAPREx), which is funded by the Carnegie Corporation of New York, for a Postdoctoral Fellowship. K.K. also appreciates the Cambridge-Africa ALBORADA Research Fund for support and MRC African Research Leaders MR/S00520X/1 Award. S.K. wishes to thank the Carnegie BANGA-Africa Project Award for a PhD scholarship. Acknowledgments: All the authors extend their gratitude to the Department of Chemistry, UG for providing NMR facility. Conflicts of Interest: The authors declare no conflicts of interests. Author Contributions: K.K. collected mangrove plant parts and isolated the strain BRS2A-AR2. A.S.C. and M.C. identified the exact taxonomy of the strain. M.J. and H.D. provided access to facilities for mass spectrometry and data interpretation. K.K. performed chemical profiling to identify the major metabolite. S.K. and G.M.T. performed seed culture, large scale culture, isolation and purification of compound. A.K.D. performed all the biological assays. K.K. measured all NMR, IR and UV, analyzed the results and integration of data to give the complete structure of the compound. K.K. wrote the article.Peer reviewedPublisher PD

Digyaindoleacid A : 2-(1-(4-hydroxyphenyl)-3-oxobut-1-en-2-yloxy)-3-(1H-indol-3-yl)propanoic acid, a novel indole alkaloid

Funding Information: Funding: K.K. wishes to thank the Centre for African Wetlands (CAW), University of Ghana, for providing seed funding to enable the collection of sediments for microbe isolation and The World Academy of Sciences (TWAS) Research Grant Award_17-512 RG/CHE/AF/AC_G. K.K. is also very grateful to the Cambridge-Africa Partnership for Research Excellence (CAPREx), which is funded by the Carnegie Corporation of New York, for a postdoctoral fellowship. K.K. also appreciates the Cambridge–Africa ALBORADA Research Fund for support and the Medical Research Council (MRC)/Department for International Development (DFID) African Research Leaders MR/S00520X/1 Award. S.K. wishes to thank the Carnegie Building a New Generation of Academics (BANGA)-Africa Project Award for a PhD scholarship and M.T. is grateful for an MPhil full scholarship from the TWAS Research Grant Award_17-512 RG/CHE/AF/AC_G.Peer reviewe

Paenidigyamycin g : 1-acetyl-2,4-dimethyl-3-phenethyl-1H-imidazol-3-ium

Author Contributions: K.K. and H.D. collected mangrove sediments and isolated the strain DE2SH. A.S.C. and M.C. identified the exact taxonomy of the strain after K.K. isolated DNA and whole genome sequenced the strain. M.J. and H.D. provided access to facilities for mass spectrometry and data interpretation. K.K. performed chemical profiling to identify the major metabolites. S.K., G.M.T. and T.M. performed seed culture, large scale culture, isolation and purification of compound. K.K. measured all NMR, IR and UV, analyzed the results and integration of data to give the complete structure of the compound. K.K., S.K. and G.M.T. wrote the initial draft of the article which was edited and finalized by all the authors. Funding: KK wishes to thank the Centre for African Wetlands (CAW), University of Ghana, for providing seed funding to enable the collection of soil samples for microbe isolation and a TWAS Research Grant Award_17-512 RG/CHE/AF/AC_G. K.K. is also very grateful to the Cambridge-Africa Partnership for Research Excellence (CAPREx), which is funded by the Carnegie Corporation of New York, for a Postdoctoral Fellowship. K.K. also appreciates the Cambridge-Africa ALBORADA Research Fund for support. K.K., H.D. and M.J. are grateful for this research which is jointly funded by the UK Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID African Research Leaders Award (MR/S00520X/1). S.K. wishes to thank the Carnegie BANGA-Africa Project Award for a PhD scholarship and M.T. is grateful for an MPhil full scholarship from TWAS Research Grant Award_17-512 RG/CHE/AF/AC_G. Acknowledgments: All the authors extend their gratitude to the Department of Chemistry, UG for providing NMR facility. Conflicts of Interest: The authors declare no conflicts of interestsPeer reviewedPublisher PD

Paenidigyamycin A, Potent Antiparasitic Imidazole Alkaloid from the Ghanaian Paenibacillus sp. DE2SH

KK wishes to thank the Centre for African Wetlands (CAW), University of Ghana, for providing seed funding to enable the collection of soil samples for microbe isolation and a TWAS Research Grant Award_17-512 RG/CHE/AF/AC_G. K.K. is also very grateful to the Cambridge-Africa Partnership for Research Excellence (CAPREx), which is funded by the Carnegie Corporation of New York, for a Postdoctoral Fellowship. K.K. also appreciates the Cambridge-Africa ALBORADA Research Fund for support and MRC African Research Leaders MR/S00520X/1 Award. S.K. wishes to thank the Carnegie BANGA-Africa Project Award for a PhD scholarship.Peer reviewedPublisher PD

N-(Isobutyl)-3,4-methylenedioxy Cinnamoyl Amide

The plant Zanthoxylum zanthoxyloides (Lam.) Zepern. & Timler is one of the most important medicinal species of the genus Zanthoxylum on the African continent. It is used in the treatment and management of parasitic diseases in sub-Saharan Africa. These properties have inspired scientists to investigate species within the genus for bioactive compounds. However, a study, which details a spectroscopic, spectrometric and bioactivity guided extraction and isolation of antiparasitic compounds from the genus Zanthoxylum is currently non-existent. Tortozanthoxylamide (1), which is a derivative of the known compound armatamide was isolated from Z. zanthoxyloides and the full structure determined using UV, IR, 1D/2D-NMR and high-resolution liquid chromatography tandem mass spectrometry (HRESI-LC-MS) data. When tested against Trypanosoma brucei subsp. brucei, the parasite responsible for animal African trypanosomiasis in sub-Saharan Africa, 1 (IC50 7.78 µM) was just four times less active than the commercially available drug diminazene aceturate (IC50 1.88 µM). Diminazene aceturate is a potent drug for the treatment of animal African trypanosomiasis. Tortozanthoxylamide (1) exhibits a significant antitrypanosomal activity through remarkable alteration of the cell cycle in T. brucei subsp. brucei, but it is selectively non-toxic to mouse macrophages RAW 264.7 cell lines. This suggests that 1 may be considered as a scaffold for the further development of natural antitrypanosomal compounds

Digyaindoleacid A: 2-(1-(4-Hydroxyphenyl)-3-oxobut-1-en-2-yloxy)-3-(1H-indol-3-yl)propanoic Acid, a Novel Indole Alkaloid

Digyaindoleacid A (1) is one of the novel alkaloids produced by the Ghanaian Paenibacillus sp. DE2SH (GenBank Accession Number: MH091697) isolated from the mangrove rhizosphere soils of the Pterocarpus santalinoides tree growing in the wetlands of the Digya National Park, Brong Ahafo Region, Ghana. This compound was isolated on HPLC at tR ≈ 60 min and its structure determined by MS, 1D, and 2D-NMR data. When tested against Trypanosoma brucei subsp. brucei strain GUTat 3.1, 1 produced a half-maximal inhibitory concentration (IC50) 5.21 μM compared to the standard diminazene aceturate (IC50 = 1.86 μM). In the presence of normal mouse macrophages RAW 264.7, 1 displayed a higher selectivity towards T. brucei subsp. brucei (selectivity indices (SI) = 30.2) with low toxicity. This result is interesting given that the drug diminazene aceturate is considerably toxic and 1 is a natural product isolate. The structure of 1 incorporates the backbone of the amino acid tryptophan which is crucial in the metabolism of Trypanosoma brucei subsp. brucei strain GUTat 3.1. It is possible that 1, could interfere with the normal uptake and metabolism of tryptophan in the parasite. However, 1 (IC50 = 135.41 μM) produced weak antileishmanial activity when tested against Leishmania donovani (Laveran and Mesnil) Ross (D10)