Synthesis, Antiplasmodial and Antitrypanosomal Evaluation of a Series of Novel 2-Oxoquinoline-based Thiosemicarbazone Derivatives

Darrel, Oliver T.; Hulushe, Siyabonga T.; Mtshare, Thanduxolo E.; Beteck, Richard M.; Isaacs, Michelle; Laming, Dustin; Krause, Rui W. M.; Khanye, Setshaba D.

doi:10.17159/0379-4350/2018/v71a23

Cited by 8 publications

(2 citation statements)

References 28 publications

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“…An antimalarial evaluation was performed against the chloroquine sensitive strain of P. falciparum (3D7) using the parasite lactate dehydrogenase (pLDH) assay as previously reported [38]. Parasites were seeded at 2% parasitemia and 1% hematocrit in 96 well plates and were incubated with 20 µM of the test compounds for 48 h in culture medium consisting of Rosell Park Memorial Institute (RPMI 1640; Lonza, Basel, Switzerland) containing 25 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), supplemented with 0.5% ( w / v ) Albumax II, 22 mM glucose, 0.65 mM hypoxanthine, 0.05mg/mL gentamicin, and 1% ( v / v ) human erythrocytes, at 37 °C under an atmosphere of 5% CO 2 , 5% O 2 , and 90% N 2 .…”

Section: Methodsmentioning

confidence: 99%

Anti-Trypanosomal and Antimalarial Properties of Tetralone Derivatives and Structurally Related Benzocycloalkanones

et al. 2019

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Background and objectives: Sleeping sickness and malaria alike are insect-borne protozoan diseases that share overlapping endemic areas in sub-Saharan Africa. The causative agent for malaria has developed resistance against all currently deployed anti-malarial agents. In the case of sleeping sickness, the currently deployed therapeutic options are limited in efficacy and activity spectra, and there are very few drug candidates in the development pipeline. Thus, there is a need to search for new drug molecules with a novel mode of actions. Materials and Methods: In the current study, an in vitro screening of a library of tetralone derivatives and related benzocycloalkanones was effected against T. b. brucei and P. falciparum. Results: Several hits with low micromolar activity (0.4–8 µM) against T. b. brucei were identified. Conclusions: The identified hits have a low molecular weight (<280 Da), a low total polar surface area (<50 Å²), and a defined structure activity relationship, which all make them potential starting points for further hit optimization studies.

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Section: Methodsmentioning

confidence: 99%

Anti-Trypanosomal and Antimalarial Properties of Tetralone Derivatives and Structurally Related Benzocycloalkanones

et al. 2019

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“…Further preliminary structure-activity relationship (SAR) investigations were conducted through Molecular hybridization, which combines two or more dissimilar pharmacophoric subunits to improve efficacy and other pharmaceutical profiles is becoming an attractive approach to design novel biologically active compounds [39][40][41]. Considering our ongoing research interests to identify and develop new antiparasitic compounds [42][43][44], we employed a molecular hybridization approach to design a target series of chalcone derivatives ( Figure 2) featuring A ring with hydroxyl and bromine substituents at position 2 and 5, respectively, and arylpyrrole containing B ring system. Herein, we wish to report the synthesis of a representative series of new and non-toxic arylpyrrole-based chalcone derivatives, along with their in vitro anti-trypanosomal effects against the nagana T. b. brucei strain.…”

Section: Chemical Synthesismentioning

confidence: 99%

Synthesis, Structure and In Vitro Anti-Trypanosomal Activity of Non-Toxic Arylpyrrole-Based Chalcone Derivatives

et al. 2020

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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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In silico investigation of falcipain-2 inhibition by hybrid benzimidazole-thiosemicarbazone antiplasmodial agents: A molecular docking, molecular dynamics simulation, and kinetics study

Nkungli

Fouégué²,

Tasheh

et al. 2023

Mol Divers

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The emergence of artemisinin-resistant variants of Plasmodium falciparum necessitates the urgent search for novel antimalarial drugs. In this regard, an in silico study to screen antimalarial drug candidates from a series of benzimidazole-thiosemicarbazone hybrid molecules with interesting antiplasmodial properties and explore their falcipain-2 (FP2) inhibitory potentials has been undertaken herein. FP2 is a key cysteine protease that degrades hemoglobin in Plasmodium falciparum and is an important biomolecular target in the development of antimalarial drugs. Pharmacokinetic properties, ADMET profiles, MM/GBSA-based binding free energies, reaction mechanisms, and associated barrier heights have been investigated. DFT, molecular dynamics simulation, molecular docking, and ONIOM methods were used. From the results obtained, four 4 N -substituted derivatives of the hybrid molecule ( E )-2-(1-(5-chloro-1 H -benzo[ d ]imidazol-2-yl)ethylidene)hydrazine-1-carbothioamide (1A) denoted 1B, 1C, 1D, and 1E are drug-like and promising inhibitors of FP2, exhibiting remarkably small inhibitory constants (5.94 × 10 –14 − 2.59 × 10 –04 M) and favorable binding free energies (−30.32 to −17.17 kcal/mol). Moreover, the ONIOM results have revealed that 1B and possibly 1C and 1D may act as covalent inhibitors of FP2. The rate-determining step of the thermodynamically favorable covalent binding mechanism occurs across a surmountable barrier height of 24.18 kcal/mol in water and 28.42 kcal/mol in diethyl ether. Our findings are useful for further experimental investigations on the antimalarial activities of the hybrid molecules studied. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1007/s11030-022-10594-3.

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Synthesis, Antiplasmodial and Antitrypanosomal Evaluation of a Series of Novel 2-Oxoquinoline-based Thiosemicarbazone Derivatives

Cited by 8 publications

References 28 publications

Anti-Trypanosomal and Antimalarial Properties of Tetralone Derivatives and Structurally Related Benzocycloalkanones

Anti-Trypanosomal and Antimalarial Properties of Tetralone Derivatives and Structurally Related Benzocycloalkanones

Synthesis, Structure and In Vitro Anti-Trypanosomal Activity of Non-Toxic Arylpyrrole-Based Chalcone Derivatives

In silico investigation of falcipain-2 inhibition by hybrid benzimidazole-thiosemicarbazone antiplasmodial agents: A molecular docking, molecular dynamics simulation, and kinetics study

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