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Abstract: Hydroxy-substituted anthraquinones are among the most important derivatives in organic synthesis. The attractive biological properties of these compounds are relevant to many therapeutic areas that are of use in clinical applications. In this study synthesized several amino-substituted anthraquinones were synthesized from 1,4-dihydroxyanthraquinone using a modified Marschalk reaction. Moreover, 1,4,5-trihydroxyanthraquinone was synthesized from anacardic acid, an agro-waste from the cashew industry. The in-vitro screening of the compounds against Trypanosoma brucei parasites revealed noteworthy activity with reasonable selectivity against human cell lines. A molecular docking study was performed to analyze the synthesized compounds' modes of interaction to the trypanothione reductase's active site. Visual inspections examined the docked poses, and test compounds displayed a good binding affinity with the receptor protein. This in vitro/ molecular docking evaluation suggests that substituted 1,4-dihydroxyanthraquinone derivative can be promising starting structures in the search for active drugs against trypanosomiasis.

Previous research shows that the root and bark extracts of Euclea natalensis have antiplasmodial activity, but the leaves have not been examined yet. This study investigated the phytochemical, antiplasmodial, and cytotoxic properties of the plant leaves. The activity against 3D7 Plasmodium falciparum was determined using the parasite lactate dehydrogenase assay, and the cytotoxicity against Vero and HeLa cells was evaluated using the MTT and resazurin assays, respectively. The bioactive compounds were isolated by chromatography, and their structures were established with spectroscopic and spectrometric techniques. The extract showed antiplasmodial activity (IC

In this study, we synthesized novel nitro quinolone‐based compounds and tested them in vitro against a panel of Gram‐positive and Gram‐negative pathogens including Mycobacterium tuberculosis (MTB), Pseudomonas aeruginosa , Acinetobacter baumannii , Klebsiella pneumonia , Staphylococcus aureus , and Escherichia coli for antibacterial activities and also against HeLa cells for overt cytotoxicity. Compound 8e was identified as a non‐toxic, potent hit with selective activity (MIC90 ˂ 0.24 µm ) against MTB. 8e , however, showed no activity against DprE1 mutant, suggesting DprE1 as the likely target for this compound class

The regulation of human Arf1 GTPase activity by ArfGEFs that stimulate GDP/GTP exchange and ArfGAPs that mediate GTP hydrolysis has attracted attention for the discovery of Arf1 inhibitors as potential anti-cancer agents. The malaria parasite Plasmodium falciparum encodes a Sec7 domain-containing protein - presumably an ArfGEF - and two putative ArfGAPs, as well as an Arf1 homologue (PfArf1) that is essential for blood-stage parasite viability. However, ArfGEF and ArfGAP-mediated activation/deactivation of PfArf1 has not been demonstrated. In this study, we established an in vitro colorimetric microtiter plate-based assay to detect the activation status of truncated human and P. falciparum Arf1 and used it to demonstrate the activation of both proteins by the Sec7 domain of ARNO, their deactivation by the GAP domain of human ArfGAP1 and the inhibition of the respective reactions by the compounds SecinH3 and QS11. In addition, we found that the GAP domains of both P. falciparum ArfGAPs have activities equivalent to that of human ArfGAP1, but are insensitive to QS11. Library screening identified a novel inhibitor which selectively inhibits one of the P. falciparum GAP domains (IC50 4.7 µM), suggesting that the assay format is suitable for screening compound collections for inhibitors of Arf1 regulatory proteins.

Previous results indicated that the methanol extract of

Recently we reported the results of a screen of the Pathogen Box in which we identified 4-(2-amino-5-(4-(methylsulfonyl) phenyl) pyridin-3-yl)-2-methoxyphenol (MMV010576, 1) as our priority antitrypanosomal hit. This compound had previously been identified as a potent and selective antiplasmodial agent, where a focused optimization campaign, resulted in a medium-sized library of compounds, with favorable drug-like properties, one of which (MMV048, 2, 5-(4-(methylsulfonyl)phenyl)-6'-(trifluoromethyl)-[3,3'-bipyridin]-2-amine) is currently undergoing clinical trials for malaria. Accordingly, we investigated this library, in order to elucidate structural activity relationship details of this class of compounds as inhibitors of Trypanosoma brucei. Our study has identified several structural features important for antitrypanosomal activity, which are distinct from those required for antiplasmodial activity. Results from this study can be exploited to develop potent antitrypanosomal agents.

Ozoroa obovata (Oliv.) R.A. Fern. var. obovata found in KwaZulu-Natal in South Africa was investigated for phytochemical constituents, and for antiplasmodial and cytotoxic effects. The plant leaves were collected from the University of KwaZulu-Natal (UKZN) arboretum on the Pietermaritzburg Campus, in March 2019. The inhibitory activity against 3D7 Plasmodium falciparum was determined using the parasite lactate dehydrogenase (pLDH) assay and cytotoxicity against HeLa cells was evaluated using the resazurin assay. The bioactive compounds were isolated by chromatographic purification and their structures were established with spectroscopic and spectrometric techniques. The plant leaf extract displayed significant antiplasmodial activity at 50 μg/mL and was also cytotoxic against HeLa cells. Chromatographic purification of the extract led to the isolation of two biflavonoids, four flavonoid glycosides, a steroid glycoside, and a megastigmene derivative. The compounds displayed antiplasmodial and antiproliferative activities at 50 μg/mL but the activity was substantially reduced at 10 μg/mL. The activities and compounds are being reported in O. obovata for the first time.

A tailored series of coumarin-based ferrocenyl 1,3-oxazine hybrid compounds was synthesized and investigated for potential antiparasitic activity, drawing inspiration from the established biological efficacy of the constituent chemical motifs. The structural identity of the synthesized compounds was confirmed by common spectroscopic techniques: NMR, HRMS and IR. Biological evaluation studies reveal that the compounds exhibit higher in vitro antiparasitic potency against the chemosensitive malarial strain (3D7 P. falciparum) over the investigated trypanosomiasis causal agent (T. b. brucei 427) with mostly single digit micromolar IC50 values. When read in tandem with the biological performance of previously reported structurally similar non-coumarin, phenyl derivatives (i.e., ferrocenyl 1,3-benzoxazines and α-aminocresols), structure-activity relationship analyses suggest that the presence of the coumarin nucleus is tolerated for biological activity though this may lead to reduced efficacy. Preliminary mechanistic studies with the most promising compound (11b) support hemozoin inhibition and DNA interaction as likely mechanistic modalities by which this class of compounds may act to produce plasmocidal and antitrypanosomal effects.

Malaria elimination can benefit from time and cost-efficient approaches for antimalarials such as drug repurposing. In this work, 796 DrugBank compounds were screened against 36 Plasmodium falciparum targets using QuickVina-W. Hits were selected after rescoring using GRaph Interaction Matching (GRIM) and ligand efficiency metrics: surface efficiency index (SEI), binding efficiency index (BEI) and lipophilic efficiency (LipE). They were further evaluated in Molecular dynamics (MD). Twenty-five protein–ligand complexes were finally retained from the 28,656 (36 × 796) dockings. Hit GRIM scores (0.58 to 0.78) showed their molecular interaction similarity to co-crystallized ligands. Minimum LipE (3), SEI (23) and BEI (7) were in at least acceptable thresholds for hits. Binding energies ranged from −6 to −11 kcal/mol. Ligands showed stability in MD simulation with good hydrogen bonding and favorable protein–ligand interactions energy (the poorest being −140.12 kcal/mol). In vitro testing showed 4 active compounds with two having IC50 values in the single-digit μM range.

Previous results indicated that the methanol extract of Gardenia thunbergia has antiplasmodial activity but no compounds have ever been isolated from the plant. Therefore, this study aimed to investigate the phytochemical and antiplasmodial properties of the plant. The methanol leaf extract of G. thunbergia inhibited Plasmodium falciparum at 50 µg/mL (> 80% inhibition) and was not cytotoxic against HeLa cells. Chromatographic purification of the extract afforded a new saponin and eight other known compounds. The saponin and two flavonoid glycosides displayed non-selective antiplasmodial activity at 50 µg/mL but the activities were diminished at 10 µg/mL. The presence of the isolated compounds in the leaf extract of G. thunbergia could account for the folkloric use of the plant in treating malaria.

International audience; The conjugation of organometallic complexes to known bioactive organic frameworks is a proven strategy revered for devising new drug molecules with novel modes of action. This approach holds great promise for the generation of potent drug leads in the quest for therapeutic chemotypes with the potential to overcome the development of clinical resistance. Herein, we present the in vitro antiplasmodial and antiproliferative investigation of ferrocenyl α‐aminocresol conjugates assembled by amalgamation of the organometallic ferrocene unit and an α‐aminocresol scaffold possessing antimalarial activity. The compounds pursued in the study exhibited higher toxicity towards the chemosensitive (3D7) and ‐resistant (Dd2) strains of the Plasmodium falciparum parasite than to the human HCC70 triple‐negative breast cancer cell line. Indication of cross‐resistance was absent for the compounds evaluated against the multi‐resistant Dd2 strain. Structure‐activity analysis revealed that the phenolic hydroxy group and rotatable σ bond between the α‐carbon and NH group of the α‐amino‐o‐cresol skeleton are crucial for the biological activity of the compounds. Spectrophotometric techniques and in silico docking simulations performed on selected derivatives suggest that the compounds show a dual mode of action involving hemozoin inhibition and DNA interaction via minor‐groove binding. Lastly, compound 9 a, identified as a possible lead, exhibited preferential binding for the plasmodial DNA isolated from 3D7 P. falciparum trophozoites over the mammalian calf thymus DNA, thereby substantiating the enhanced antiplasmodial activity of the compounds. The presented research demonstrates the strategy of incorporating organometallic complexes into known biologically active organic scaffolds as a viable avenue to fashion novel multimodal compounds with potential to counter the development drug resistance.

Human African trypanosomiasis is a vector-borne tropical disease of African origin. Presently, due to human migration and climate change, the disease might present global health and economic burdens as current chemotherapy of trypanosomiasis remains a challenge due to limited existing drugs, which are of poor efficacy, cause severe adverse events and are very costly. Recently, Beteck and co-workers identified a small library of 1,3,6-substituted non-fluoroquinolones that showed moderate to weak trypanocidal activity without cytotoxic effects. The current study further explored SARs of the quinolone scaffold in search for more potent trypanocidal agents. Fifteen novel quinolone derivatives bearing a heteroarylidene moiety at positon-6 and varied chemical entities at positions −1 and −3 of the quinolone scaffold were synthesized and evaluated in vitro for antitrypanosomal activity. The compounds exhibit exceptionally good antitrypanosomal activity with IC50 values in the low-micromolar to sub-micromolar range (0.08–15.26 μM), with compound 6d being the most active having an IC50 value of 80 nM against T.b. brucei. Compounds in this study generally have molecular weight less than 600Da, ClogP value of 2–4 and a BBB score of 1–5, hence they could be potentially effective against both stages of trypanosomiasis.