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Photo-and thermoresponsive N-salicylideneaniline derivatives: solid-state studies and structural aspects

  • Authors: Hulushe, Siyabonga T , Malan, Frederick P , Hosten, Eric C , Lobb, Kevin A , Khanye, Setshaba D , Watkins, Gareth M
  • Date: 2022
  • Subjects: To be catalogued
  • Language: English
  • Type: text , article
  • Identifier: http://hdl.handle.net/10962/451137 , vital:75021 , xlink:href="https://pubs.rsc.org/en/content/articlehtml/2022/nj/d1nj03056f"
  • Description: N-Salicylideneaniline (SA) and its derivatives are known to possess chromism upon exposure to external stimuli. Herein, we present mechanochemical synthesis of a series of photo-and thermoresponsive SAderivatives and report on solid-state stabilisation of their tautomeric forms either by change in temperature or by photoirradiation. The influence of UV light on proton transfer between the enol-imine (EI) and keto-amine (KA) forms was investigated at l1 = 254 and l2 = 365 nm. Differential scanning calorimetry (DSC) measurements provided extra information on the thermodynamic relationship between the prototropic tautomers, and their exposition to liquid nitrogen, combined with variable temperature single-crystal X-ray diffraction (VT-SCXRD) and spectroscopic data, ascertained structural reasons for the intrinsic thermo-optical properties of the compounds. A series of structural determinations between 150 and 300 K further shed light on the thermomechanical behaviour exhibited by the thermoresponsive compounds. By virtue of calorimetry we were able to demonstrate proton transfer via the intramolecular ON hydrogen bond over the temperature range 193–453 K. This present work demonstrates the importance of applying complementary analytical techniques and appropriate approaches for understanding the switching behaviour between the EI and KA forms. Furthermore, the assertion that it is predominantly the planarity (j o 251) that determines thermochromaticity is questioned.
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  • Date Issued: 2022

Arylquinolinecarboxamides: Synthesis, in vitro and in silico studies against Mycobacterium tuberculosis

  • Authors: Bokosi, Fostino R B , Beteck, Richard M , Jordaan, Audrey , Seldon, Ronnett , Warner, Digby F , Tshiwawa, Tendamudzimu , Lobb, Kevin A , Khanye, Setshaba D
  • Date: 2021
  • Subjects: To be catalogued
  • Language: English
  • Type: text , article
  • Identifier: http://hdl.handle.net/10962/451064 , vital:75015 , xlink:href="https://doi.org/10.1002/jhet.4340"
  • Description: A series of fourteen 6-substituted-2-(methoxyquinolin-3-yl) methyl)-N-(pyridin-3-ylmethyl) benzamides was prepared from commercially available anilines infive simple and convenient synthetic steps. The structures of all new productswere confirmed by routine spectroscopic methods: IR,1Hand13 CNMR,andHRMS (electrospray ionization). The resulting arylquinolinecarboxamides weresubjected to biological screening assay forin vitroinhibitory activity againstMyco-bacterium tuberculosis (Mtb) H37Rv strain. Several compounds exhibited modestantitubercular activity with compounds8–11,15and19exhibiting MIC90valuesin the range of 32–85μM. The antitubercular data suggested that inhibition ofMtbcan be imparted by the introduction of a non-polar substituent on C-6 of thequinoline scaffold. Further, to understandthepossiblemodeofactionoftheseries, the reported compounds and bedaquiline were subjected toin silicodock-ing studies againstMtbATPase to determine their potential to interfere with themycobacterial adenosine triphosphate (ATP) synthase. The results showed thatthese compounds have the potential toserve as antimycobacterial agents.In silicoADME pharmacokinetic prediction results showed the ability of thesearylquinolinecarcboxamides to be absorbed, distributed, metabolized andexcreted efficiently.
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  • Date Issued: 2021

Repurposing a polymer precursor: Synthesis and in vitro medicinal potential of ferrocenyl 1, 3-benzoxazine derivatives

  • Authors: Mbaba, Mziyanda , Dingle, Laura M K , Cash, Devon , de la Mare, Jo-Anne , Laming, Dustin , Taylor, Dale , Hoppe, Heinrich C , Edkins, Adrienne L , Khanye, Setshaba D
  • Date: 2020
  • Language: English
  • Type: text , article
  • Identifier: http://hdl.handle.net/10962/165395 , vital:41240 , https://doi.org/10.1016/j.ejmech.2019.111924
  • Description: Cancer and malaria remain relevant pathologies in modern medicinal chemistry endeavours. This is compounded by the threat of development of resistance to existing clinical drugs in use as first-line option for treatment of these diseases. To counter this threat, strategies such as drug repurposing and hybridization are constantly adapted in contemporary drug discovery for the expansion of the drug arsenal and generation of novel chemotypes with potential to avert or delay resistance. In the present study, a polymer precursor scaffold, 1,3-benzoxazine, has been repurposed by incorporation of an organometallic ferrocene unit to produce a novel class of compounds showing in vitro biological activity against breast cancer, malaria and trypanosomiasis.
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  • Date Issued: 2020

Synthesis, characterization and biological activity of some Dithiourea Derivatives:

Synthesis, structure and in vitro anti-trypanosomal activity of non-toxic Arylpyrrole-Based Chalcone derivatives:

  • Authors: Zulu, Ayanda I , Oderinlo, Ogunyemi O , Kruger, Cuan , Isaacs, Michelle , Hoppe, Heinrich C , Smith, Vincent J , Veale, Clinton G L , Khanye, Setshaba D
  • Date: 2020
  • Language: English
  • Type: text , article
  • Identifier: http://hdl.handle.net/10962/179017 , vital:40096 , https://doi.org/10.3390/molecules25071668
  • Description: With an intention of identifying chalcone derivatives exhibiting anti-protozoal activity, a cohort of relatively unexplored arylpyrrole-based chalcone derivatives were synthesized in moderate to good yields. The resultant compounds were evaluated in vitro for their potential activity against a cultured Trypanosoma brucei brucei 427 strain. Several compounds displayed mostly modest in vitro anti-trypanosomal activity with compounds 10e and 10h emerging as active candidates with IC50 values of 4.09 and 5.11 µM, respectively. More importantly, a concomitant assessment of their activity against a human cervix adenocarcinoma (HeLa) cell line revealed that these compounds are non-toxic.
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  • Date Issued: 2020

The in vitro antiplasmodial and antiproliferative activity of new ferrocene-based α-aminocresols targeting hemozoin inhibition and DNA interaction:

  • Authors: Mbaba, Mziyanda , Dingle, Laura M K , Swart, Tarryn , Cash, Devon , Laming, Dustin , de la Mare, Jo-Anne , Taylor, Dale , Hoppe, Heinrich C , Biot, Christophe , Edkins, Adrienne L , Khanye, Setshaba D
  • Date: 2020
  • Language: English
  • Type: text , article
  • Identifier: http://hdl.handle.net/10962/149347 , vital:38827 , https://0-doi.org.wam.seals.ac.za/10.1002/cbic.202000132
  • Description: Compounds incorporating ferrocene in a aminocresol scaffold showed antiplasmodial and anticancer activity. SAR studies revealed that an OH group and rotatable C–NH bond are vital for biological activity, with spectrophotometric techniques and docking simulations suggesting a dual mode of action involving hemozoin inhibition and DNA interaction. Targeting multiple pathways could delay the development of clinical resistance.
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  • Date Issued: 2020

Quinolone-isoniazid hybrids: Synthesis and preliminary in vitro cytotoxicity and anti-tuberculosis evaluation

  • Authors: Beteck, Richard M , Seldon, Ronnett , Khanye, Setshaba D , Legoabe, Lesetja J , Hoppe, Heinrich C , Laming, Dustin , Jordaan, Audrey , Warner, Digby F
  • Date: 2019
  • Language: English
  • Type: text , article
  • Identifier: http://hdl.handle.net/10962/123151 , vital:35410 , https://doi.org/10.1039/C8MD00480C
  • Description: Herein, we propose novel quinolones incorporating an INH moiety as potential drug templates against TB. The quinolone-based compounds bearing an INH moiety attached via a hydrazide–hydrazone bond were synthesised and evaluated against Mycobacterium tuberculosis H37Rv (MTB). The compounds were also evaluated for cytotoxicity against HeLa cell lines. These compounds showed significant activity (MIC90) against MTB in the range of 0.2–8 μM without any cytotoxic effects. Compounds 10 (MIC90; 0.9 μM), 11 (MIC90; 0.2 μM), 12 (MIC90; 0.8 μM) and compound 15 (MIC90; 0.8 μM), the most active compounds in this series, demonstrate activities on par with INH and superior to those reported for the fluoroquinolones. The SAR analysis suggests that the nature of substituents at positions −1 and −3 of the quinolone nucleus influences anti-MTB activity. Aqueous solubility evaluation and in vitro metabolic stability of compound 12 highlights favourable drug-like properties for this compound class.
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  • Date Issued: 2019

A New Synthetic Method for Tetraazatricyclic Derivatives and Evaluation of Their Biological Properties

  • Authors: Odame, Felix , Betz, Richard , Hosten, Eric C , Krause, Jason , Isaacs, Michelle , Hoppe, Heinrich C , Khanye, Setshaba D , Sayed, Yasien , Frost, P Carminita , Lobb, Kevin A , Tshentu, Zenixole R
  • Date: 2018
  • Language: English
  • Type: text , article
  • Identifier: http://hdl.handle.net/10962/123189 , vital:35413 , https://doi.org/10.1002/slct.201802930
  • Description: Herein, we propose novel quinolones incorporating an INH moiety as potential drug templates against TB. The quinolone-based compounds bearing an INH moiety attached via a hydrazide–hydrazone bond were synthesised and evaluated against Mycobacterium tuberculosis H37Rv (MTB). The compounds were also evaluated for cytotoxicity against HeLa cell lines. These compounds showed significant activity (MIC90) against MTB in the range of 0.2–8 μM without any cytotoxic effects. Compounds 10 (MIC90; 0.9 μM), 11 (MIC90; 0.2 μM), 12 (MIC90; 0.8 μM) and compound 15 (MIC90; 0.8 μM), the most active compounds in this series, demonstrate activities on par with INH and superior to those reported for the fluoroquinolones. The SAR analysis suggests that the nature of substituents at positions −1 and −3 of the quinolone nucleus influences anti-MTB activity. Aqueous solubility evaluation and in vitro metabolic stability of compound 12 highlights favourable drug-like properties for this compound class.
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  • Date Issued: 2018

Expanding the SAR of Nontoxic Antiplasmodial Indolyl-3-ethanone Ethers and Thioethers:

  • Authors: Lunga, Mayibongwe J , Chisango, Ruramai L , Weyers, Carli , Isaacs, Michelle , Taylor, Dale , Edkins, Adrienne L , Khanye, Setshaba D , Hoppe, Heinrich C , Veale, Clinton G L
  • Date: 2018
  • Language: English
  • Type: text , article
  • Identifier: http://hdl.handle.net/10962/164389 , vital:41114 , DOI: 10.1002/cmdc.201800235
  • Description: Despite major strides in reducing Plasmodium falciparum infections, this parasite still accounts for roughly half a million annual deaths. This problem is compounded by the decreased efficacy of artemisinin combination therapies. Therefore, the development and optimisation of novel antimalarial chemotypes is critical. In this study, we describe our strategic approach to optimise a class of previously reported antimalarials, resulting in the discovery of 1-(5-chloro-1H-indol-3-yl)-2-[(4-cyanophenyl)thio]ethanone (13) and 1-(5-chloro-1H-indol-3-yl)-2-[(4-nitrophenyl)thio]ethanone (14), whose activity was equipotent to that of chloroquine against the P. falciparum 3D7 strain.
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  • Date Issued: 2018

New thiazolidine-2,4-dione derivatives combined with organometallic ferrocene: Synthesis, structure and antiparasitic activity

  • Authors: Oderinlo, Ogunyemi O , Tukulula, Matshawandile , Isaacs, Michelle , Taylor, Dale , Smith, Vincent J , Khanye, Setshaba D , Hoppe, Heinrich C
  • Date: 2018
  • Language: English
  • Type: text , article
  • Identifier: http://hdl.handle.net/10962/122978 , vital:35382 , https://doi.org/10.1002/aoc.4385
  • Description: Favourable physicochemical properties of an organometallic ferrocene and antiplasmodial potency of compounds containing the thiazolidine‐2,4‐dione framework (TZD‐4) prompted us to explore compounds containing both the thiazolidine‐2,4‐dione core and the ferrocenyl unit with the primary aim of identifying compounds with promising antiprotozoal activities. Thus, a new series of rationally designed ferrocene‐based thiazolidine‐2,4‐dione derivatives, containing a selection of secondary cyclic amines, was synthesised and fully characterised using standard spectroscopic techniques. The resulting compounds were screened for their antiplasmodial and antitrypanosomal activities against both the chloroquine‐resistant (Dd2) strain of Plasmodium falciparum and the Nagana Trypanosoma brucei brucei 427. The general trend that emerged indicated that the target compounds were more selective towards T. b. brucei compared to the P. falciparum parasite. Moreover, the analogues bearing methylpiperazine (8a) and piperidine (8b) rings were more active against T. b. brucei compared to hit compound TZD‐4. Except compound 8b, which appeared promising, none of the synthesised compounds showed better activity than TZD‐4 against the P. falciparum parasite. All the synthesised compounds were non‐toxic and often showed >90% viability of the HeLa cell line screened.
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  • Date Issued: 2018

Synthesis, antiplasmodial and antitrypanosomal evaluation of a series of novel 2-oxoquinoline-based thiosemicarbazone derivatives

  • Authors: Darrell, Oliver T , Hulushe, Siyabonga T , Mtshare, Thanduxolo Elihle , Beteck, Richard M , Isaacs, Michelle , Laming, Dustin , Khanye, Setshaba D , Hoppe, Heinrich C , Krause, Rui W M
  • Date: 2018
  • Language: English
  • Type: text , article
  • Identifier: http://hdl.handle.net/10962/123117 , vital:35407 , https://doi.org/10.17159/0379-4350/2018/v71a25
  • Description: Herein a series of novel thiosemicarbazones (TSCs) derived from 2-oxoquinoline scaffold is reported, and the target compounds have been successfully synthesized and characterized using standard spectroscopic techniques. The in vitro biological activities of synthesized molecules were evaluated against Plasmodium falciparum malaria parasites (strain 3D7), Trypanosoma brucei brucei parasites (strain 427) and HeLa cells. All the compounds displayed modest or no activity at a concentration of 20 μM and percentage viability of >50 % was often observed. Except for compound 9o, none of the final compounds exhibited cytotoxic effects against HeLa cells at 20 μM.
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  • Date Issued: 2018

Synthesis, in vitro cytotoxicity and trypanocidal evaluation of novel 1, 3, 6-substituted non-fluoroquinolones

  • Authors: Beteck, Richard M , Isaacs, Michelle , Khanye, Setshaba D , Hoppe, Heinrich C
  • Date: 2018
  • Language: English
  • Type: text , article
  • Identifier: http://hdl.handle.net/10962/123140 , vital:35409 , https://doi.org/10.17159/0379-4350/2018/v71a25
  • Description: Sleeping sickness (trypanosomiasis) is a neglected tropical disease that affects mostly the poorest communities in sub-Saharan Africa. Toxic side effects associated with the use of current anti-trypanosomal drugs, which in some cases kill faster than the disease itself, necessitate the search for new drugs with better safety margins. To this effect, a small library bearing different substituents at position -1, -3, and -6 of the quinolone nucleus were synthesized and evaluated in vitro against HeLa cell lines and Trypanosoma brucei brucei for cytotoxicity and trypanocidal potentials, respectively. While most of these compounds showed no cytotoxic effect, they exhibited moderate to weak anti-trypanosomal activities. The SAR studies of this series provide new information worth considering in future exploration of the quinolone scaffold in search ofmore potent and safe trypanocidal agents.
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  • Date Issued: 2018

Application of the Morita-Baylis-Hillman reaction in the synthesis of 3-[(N-cycloalkylbenzamido)methyl]-2-quinolones as potential HIV-1 integrase inhibitors

  • Authors: Sekgota, Khethobole C , Majumder, Swarup , Isaacs, Michelle , Mnkandhla, Dumisani , Hoppe, Heinrich C , Khanye, Setshaba D , Kriel, Frederik H , Coates, Judy , Kaye, Perry T
  • Date: 2017
  • Language: English
  • Type: text , article
  • Identifier: http://hdl.handle.net/10962/66178 , vital:28913 , https://doi.org/10.1016/j.bioorg.2017.09.015
  • Description: publisher version , A practicable six-step synthetic pathway has been developed to access a library of novel 3-[(N-cycloalkylbenzamido)methyl]-2-quinolones using Morita-Baylis-Hillman methodology. These compounds and their 3-[(N-cycloalkylamino)methyl]-2-quinolone precursors have been screened as potential HIV-1 integrase (IN) inhibitors. A concomitant survey of their activity against HIV-1 protease and reverse-transcriptase reveals selective inhibition of HIV-1 IN.
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  • Date Issued: 2017

Ferrocenyl and organic novobiocin derivatives: synthesis and their in vitro biological activity

  • Authors: Mbaba, Mziyanda , Mabhula, Amanda N , Boel, Natasha , Edkins, Adrienne L , Isaacs, Michelle , Hoppe, Heinrich C , Khanye, Setshaba D
  • Date: 2017
  • Language: English
  • Type: text , article
  • Identifier: http://hdl.handle.net/10962/66189 , vital:28914 , https://doi.org/10.1016/j.jinorgbio.2017.04.014
  • Description: publisher version , A focused series of novobiocin derivatives containing a ferrocene unit together with their corresponding organic novobiocin analogues have been synthesized in modest to good yields. These compounds were screened for biological activity against a chloroquine-sensitive strain of Plasmodium falciparum (3D7) and human breast cancer cell line (HCC38). With the exception of compounds 5c and 5d, the general trend observed is that incorporation of the ferrocene moiety into novobiocin scaffold resulted in compounds 6a–d/6f showing enhanced activity compared to organic analogues 5a–b and 5e–f.
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  • Date Issued: 2017

Unexpected transformations of 3-(bromoacetyl)coumarin provides new evidence for the mechanism of thiol mediated dehalogenation of α-halocarbonyls

  • Authors: Magwenzi, Faith N , Khanye, Setshaba D , Veale, Clinton G L
  • Date: 2017
  • Language: English
  • Type: text , article
  • Identifier: http://hdl.handle.net/10962/66200 , vital:28916 , https://doi.org/10.1016/j.tetlet.2017.01.082
  • Description: publisher version , The mechanism for the thiol mediated dehalogenation of α-halogenated carbonyls has remained an unresolved problem, despite its ongoing application in synthetic organic chemistry. Nakamura and co-workers first proposed that net dehalogenation occurs via sequential nucleophilic substitutions, while Israel and co-workers concluded that the rate at which dehalogenation occurred suggested that dehalogenation proceeds in a single concerted step. In this study, we investigated the debromination and nucleophilic substitution of 3-(bromoacetyl)coumarin with a variety of thiophenols, whose electron donating or withdrawing natures resulted in large variations in the degree of nucleophilic substitution and dehalogenation products, respectively. Results from these experiments, in addition to an unexpected formation of thioether containing dibenzo[b,d]pyran-6-ones from a Robinson annulation, has provided new evidence for this disputed mechanism.
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  • Date Issued: 2017

Indolyl-3-ethanone-α-thioethers: a promising new class of non-toxic antimalarial agents

  • Authors: Svogie, Archibald L , Isaacs, Michelle , Hoppe, Heinrich C , Khanye, Setshaba D , Veale, Clinton G L
  • Date: 2016
  • Language: English
  • Type: text , article
  • Identifier: http://hdl.handle.net/10962/66233 , vital:28920 , https://doi.org/10.1016/j.ejmech.2016.02.056
  • Description: publisher version , The success of chemotherapeutics in easing the burden of malaria is under continuous threat from ever-evolving parasite resistance, including resistance to artemisinin combination therapies. Therefore, the discovery of new classes of antimalarials which inhibit new biological targets is imperative to controlling malaria. Accordingly, we report here the discovery of indolyl-3-ethanone-α-thioethers, a new class of antimalarial compounds with encouraging activity. Synthesis of a focused library of compounds revealed important insight into the SAR of this class of compounds, including critical information regarding the position and chemical nature of substituents on both the thiophenol and indole rings. This investigation ultimately led to the discovery of two hit compounds (16 and 27) which exhibited nano molar in vitro antimalarial activity coupled to no observable toxicity against a HeLa cell line.
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  • Date Issued: 2016

Facile synthesis and biological evaluation of assorted indolyl-3-amides and esters from a single, stable carbonyl nitrile intermediate

  • Authors: Veale, Clinton G L , Edkins, Adrienne L , de la Mare, Jo-Anne , de Kock, Carmen , Smith, Peter J , Khanye, Setshaba D
  • Date: 2015
  • Language: English
  • Type: text , article
  • Identifier: http://hdl.handle.net/10962/66221 , vital:28919 , https://doi.org/10.1016/j.tetlet.2015.02.090
  • Description: publisher version , The synthesis of biologically relevant amides and esters is routinely conducted under complex reaction conditions or requires the use of additional catalysts in order to generate sensitive electrophilic species for attack by a nucleophile. Here we present the synthesis of different indolic esters and amides from indolyl-3-carbonyl nitrile, without the requirement of anhydrous reaction conditions or catalysts. Additionally, we screened these compounds for potential in vitro antimalarial and anticancer activity, revealing 1H-indolyl-3-carboxylic acid 3-(indolyl-3-carboxamide)aminobenzyl ester to have moderate activity against both lines.
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  • Date Issued: 2015

A ring-closing metathesis approach to eight-membered benzannelated scaffolds and subsequent internal alkene isomerizations

  • Authors: Taher, Abu , Aderibigbe, Blessing A , Morgans, Garreth L , Madeley, Lee G , Khanye, Setshaba D , Van der Westhuizen, Leandi , Fernandes, Manuel A , Smith, Vincent J , Michael, Joseph P , Green, Ivan R , Van Otterlo, Willem A L
  • Date: 2013
  • Language: English
  • Type: text , article
  • Identifier: http://hdl.handle.net/10962/66252 , vital:28925 , https://doi.org/10.1016/j.tet.2012.12.043
  • Description: publisher version , A set of eight-membered benzannelated heterocycles containing two heteroatoms (O,O, NR,NR and O,NR where R=protecting group) was synthesized by ring-closing metathesis from the corresponding ortho-bis-allyl precursors. In this manner, 7-methoxy-2,5-dihydro-1,6-benzodioxocine, 1,2,5,6-tetrahydro-1,6-benzodiazocines, 5,6-dihydro-2H-1,6-benzoxazocines and 5,6,9,10-tetrahydropyrido[2,3-b][1,4]diazocine were synthesized. A number of these compounds were then treated with the catalyst [RuClH(CO)(PPh3)3] to facilitate isomerization of the alkene into conjugation with the heteroatoms in the eight-membered ring. Quite surprisingly, an equal ratio of regioisomers was obtained, even if the heteroatoms were different.
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  • Date Issued: 2013

Cinnamoyl-Oxaborole Amides: Synthesis and Their in Vitro Biological Activity.

  • Authors: Gumbo, Maureen , Beteck, Richard M , Mandizvo, Tawanda , Seldon, Ronnett , Warner, Digby F , Hoppe, Heinrich C , Isaacs, Michelle , Laming, Dustin , Tam, Christina C , Cheng, Luisa W , Liu, Nicole , Land, Kirkwood , Khanye, Setshaba D
  • Language: English
  • Type: text , article
  • Identifier: http://hdl.handle.net/10962/122879 , vital:35362 , https://doi.org/10.3390/molecules23082038
  • Description: Due to the increased interest in their application in the treatment of infectious diseases, boron-containing compounds have received a significant coverage in the literature. Herein, a small set of novel cinnamoly-oxaborole amides were synthesized and screened against nagana Trypanosoma brucei brucei for antitrypanosomal activity. Compound 5g emerged as a new hit with an in vitro IC50 value of 0.086 μM against T. b. brucei without obvious inhibitory activity against HeLa cell lines. The same series was also screened against other human pathogens, including Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), for which moderate to weak activity (10 to >125 μM) was observed. Similarly, these compounds exhibited moderate activity against the human protozoal pathogen Trichomonas vaginalis with no observed effect on common microbiome bacterial species. The cross-species inhibitory activity presents the possibility of these compounds serving as broad-spectrum antibiotics for these prevalent three human pathogens.
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Expanding the SAR of Nontoxic Antiplasmodial Indolyl-3-ethanone Ethers and Thioethers.

  • Authors: Lunga, Mayibongwe J , Chisango, Ruramai Lissa , Weyers, Carli , Isaacs, Michelle , Taylor, Dale , Edkins, Adrienne L , Khanye, Setshaba D , Hoppe, Heinrich C , Veale, Clinton G L
  • Language: English
  • Type: text , article
  • Identifier: http://hdl.handle.net/10962/122908 , vital:35370 , https://doi.org/10.1002/cmdc.201800235
  • Description: Despite major strides in reducing Plasmodium falciparum infections, this parasite still accounts for roughly half a million annual deaths. This problem is compounded by the decreased efficacy of artemisinin combination therapies. Therefore, the development and optimisation of novel antimalarial chemotypes is critical. In this study, we describe our strategic approach to optimise a class of previously reported antimalarials, resulting in the discovery of 1‐(5‐chloro‐1H‐indol‐3‐yl)‐2‐[(4‐cyanophenyl)thio]ethanone (13) and 1‐(5‐chloro‐1H‐indol‐3‐yl)‐2‐[(4‐nitrophenyl)thio]ethanone (14), whose activity was equipotent to that of chloroquine against the P. falciparum 3D7 strain. Furthermore, these compounds were found to be nontoxic to HeLa cells as well as being non‐haemolytic to uninfected red blood cells. Intriguingly, several of our most promising compounds were found to be less active against the isogenic NF54 strain, highlighting possible issues with long‐term dependability of malarial strains. Finally compound 14 displayed similar activity against both the NF54 and K1 strains, suggesting that it inhibits a pathway that is uncompromised by K1 resistance.
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