Synthesis, in vitro Cytotoxicity and Trypanocidal Evaluation of Novel 1,3,6-Substituted Non-fluoroquinolones

Abstract

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 of more potent and safe trypanocidal agents.

New Quinolone-Based Thiosemicarbazones Showing Activity Against Plasmodium falciparum and Mycobacterium tuberculosis

“…At 20 µM, none of the compounds suppressed HeLa cell viability below 80%, suggesting that they pose little cytotoxicity risk at this concentration. Target compounds were evaluated for their potential to inhibit the growth of M. tuberculosis in vitro using middlebrook 7H9 media supplemented with casitone, glucose and tyloxpol [34]. The H37Rv strain of Mtb was deployed in this study, and rifampicin was used as a reference.…”

“…Melting points were obtained using a Reichert hot stage microscope and are reported as obtained. The starting compounds 7–10 were synthesized from the commercial accessible p -nitroacetophenone 6 as previously described in the literature [34]. Purity was determined by HPLC (Agilent, Santa Clara, CA, USA), and all compounds were confirmed to have purity >95% using a similar method previously described [35].…”

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

“…As previously described [17], HeLa cells (Cellonex, Johannesburg, South Africa) were seeded in 96-well plates at a density of 2 × 10 4 cells/well in Dulbecco’s modified Eagle’s medium (DMEM) (Lonza, Basel, Switzerland) supplemented with 10% fetal calf serum and antibiotics (penicillin/streptomycin/amphotericin B) and incubated overnight at 37 °C in a 5% CO 2 incubator. Compounds were added to the cells at a final concentration of 20 µM, and incubation continued for 24 h. The cell viability in the wells was assessed by adding 20 µL of resazurin reagent (0.135 mg/mL resazurin in phosphate-buffered saline) and reading the fluorescence (Ex560/Em590) after an additional 2–4 h incubation.…”

“…Treatment of stages 1 and 2 of T. b. rhodesiense infection is possible only with suramin and melarsoprol, respectively [16]. Moreover, these drugs are associated with severe side effects that in some cases kill faster than the disease itself [17].…”

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

“…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.…”