In Vitro Antiplasmodial Activity and Cytotoxic Effect of (Z)-2-Benzylidene-4, 6-Dimethoxybenzofuran-3(2H)-One Derivatives (original) (raw)
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Eur. J. Med. Chem., 2014
A library comprising 44 diversely substituted aurones derivatives was synthesized by straightforward aldol condensation reactions of benzofuranones and the appropriately substituted benzaldehydes. Microwave enhanced synthesis using palladium catalyzed protocols was introduced as a powerful strategy for extending the chemical space around the aurone scaffold. Additionally, Mannich-base derivatives, containing a 7-aminomethyl-6-hydroxy substitution pattern at ring A, were also prepared. Screening against the chloroquine resistant Plasmodium falciparum W2 strain identified novel aurones with IC50 values in the low micromolar range. The most potent compounds contained a basic moiety, with the ability to accumulate in acidic digestive vacuole of the malaria parasite. However, none of those aurones revealed significant activity against hemozoin formation and falcipain-2, two validated targets expressed during the blood stage of P. falciparum infection and functional in digestive vacuole of the parasite. Overall, this study highlight (i) the usefulness of aurones as platforms for synthetic procedures using palladium catalyzed protocols to rapidly deliver lead compounds for further optimization and (ii) the potential of novel aurone derivatives as promising antimalarial compounds.
European Journal of Medicinal Chemistry, 2011
From the promising results we previously obtained in quinazoline series and to complete the evaluation of the in vitro antiplasmodial activity of original 2-trichloromethylquinazolines, we synthesized new quinazolines possessing a variously substituted phenoxy group at position 4 through a simple and efficient two-step-synthesis approach. The studies of their activity toward the multi-resistant W2 Plasmodium falciparum strain and of their cytotoxicity on the human hepatocyte HepG2 cell line highlighted a hit compound (molecule 7) displaying a W2 IC 50 value of 1.1 mM and a HepG2 CC 50 value of 50 mM, comparable to chloroquine and doxycycline. Structure-activity-and toxicity relationships indicate that the trichloromethyl group plays a key role in the antiplasmodial activity of such chemical scaffold and also that the phenoxy group substitution as a direct influence on the molecules selectivity. Moreover, molecule 7 displays significant specific activity against the Plasmodium genus in comparison with Toxoplasma and does not show any mutagenic property at the Ames test.
Pharmaceuticals
The malaria parasite harbors a relict plastid called the apicoplast. Although not photosynthetic, the apicoplast retains unusual, non-mammalian metabolic pathways that are essential to the parasite, opening up a new perspective for the development of novel antimalarials which display a new mechanism of action. Based on the previous antiplasmodial hit-molecules identified in the 2-trichloromethylquinoxaline series, we report herein a structure–activity relationship (SAR) study at position two of the quinoxaline ring by synthesizing 20 new compounds. The biological evaluation highlighted a hit compound (3i) with a potent PfK1 EC50 value of 0.2 µM and a HepG2 CC50 value of 32 µM (Selectivity index = 160). Nitro-containing (3i) was not genotoxic, both in the Ames test and in vitro comet assay. Activity cliffs were observed when the 2-CCl3 group was replaced, showing that it played a key role in the antiplasmodial activity. Investigation of the mechanism of action showed that 3i presents...
Synthesis and antiplasmodial activity of some 1-azabenzanthrone derivatives
Bioorganic & Medicinal Chemistry Letters, 2013
Some synthetic 1-azabenzanthrones (7H-dibenzo [de,h]quinolin-7-ones) are weakly to moderately cytotoxic, suggesting that they might also show antiparasitic activity. We have now tested a small collection of these compounds in vitro against a chloroquine-resistant Plasmodium falciparum strain, comparing their cytotoxicity against normal human fibroblasts. Our results indicate that 5-methoxy-1-azabenzanthrone and its 2,3-dihydro analogue have low micromolar antiplasmodial activities and showed more than 10-fold selectivity against the parasite, indicating that the dihydro compound, in particular, might serve as a lead compound for further development.
Bioorganic & Medicinal Chemistry Letters, 2011
A series of original quinazolines bearing a 4-thiophenoxy and a 2-trichloromethyl group was synthesized in a convenient and efficient way and was evaluated toward its in vitro antiplasmodial potential. The series revealed global good activity against the K1-multi-resistant Plasmodium falciparum strain, especially with hit compound 5 (IC 50 = 0.9 lM), in comparison with chloroquine and doxycycline chosen as reference-drugs. Both the in vitro cytotoxicity study which was conducted on the human HepG2 cell line and the in vitro antitoxoplasmic screening against Toxoplasma gondii indicate that this series presents an interesting selective antiplasmodial profile. Structure-activity-and toxicity relationships highlight that the trichloromethyl group plays a key role in the antiplasmodial activity and also show that the modulation of the thiophenol moiety influences the toxicity/activity ratio.
MAKARA of Science Series, 2012
A unique of synthetic methods was employed to prepare 2-(4-methoxyphenyl)-4-phenyl-1,10-phenanthroline (5) derivatives from 4-methoxy-benzaldehyde (1), acetophenone (2), and 8-aminoquinoline (4) with aldol condensation and cyclization reactions. The derivatives were tested through antiplasmodial test. The synthesis of derivatives compound 5 was conducted in three steps. The 3-(4-methoxyphenyl)-1-phenylpropenone 3 was synthesized through aldol condensation of 1 and 2 which has a yield of 96.42%. The compound 5 was synthesized through cyclization of compound 4 and 3 with 84.55% yield. The derivative of compound 5 was synthesized from compound 5 using DMS and DES reagents which refluxed for 21 and 22 h, to produce (1)-N-methyl-9-(4-methoxyphenyl)-7-phenyl-1,10phenanthrolinium sulfate (6) and (1)-N-ethyl-9-(4-methoxyphenyl)-7-phenyl-1,10-phenanthrolinium sulfate (7) with 91.42 and 86.36% yields, respectively. Results of in vitro testing of antiplasmodial activity of compound 5 derivatives (i.e., compound 6 and 7) against chloroquine-resistant P. falciparum FCR3 strain showed that compound 7 had higher antimalarial activity than compounds 5 and 6. Whereas, results of in vitro testing against chloroquine-sensitive P. falciparum D10 strain showed that compound 6 has higher antimalarial activity than compounds 5 and 7. Abstrak Sintesis dan Aktivitas Antiplasmodium Senyawa Turunan 2-(4-Metoksifenil)-4-fenil-1,10-fenantrolin. Suatu metode sintesis yang unik telah digunakan dalam membuat senyawa turunan 2-(4-metoksifenil)-4-fenil-1,10-fenantrolin (5) dari 4-metoksibenzaldehida (1), asetofenon (2), dan 8-aminokuinolin (4) dengan reaksi kondensasi aldol dan reaksi siklisasi. Turunan-turunan senyawa tersebut diuji aktivitasnya melalui uji aktivitas antiplasmodial. Sintesis turunan senyawa 5 dilakukan dalam tiga tahap. Senyawa 3-(4-metoksifenil)-1-fenilpropenon 3 disintesis melalui reaksi kondensasi aldol dari senyawa 1 dan 2 dengan hasil 96,42%. Senyawa 5 disintesis melalui siklisasi senyawa 4 dan 3 dengan hasil 84,55%. Turunan senyawa 5 disintesis dari senyawa 5 menggunakan DMS dan DES yang direfluks berturut-turut selama 21 dan 22 jam untuk menghasilkan (1)-N-metil-9-(4-metoksifenil)-7-fenil-1,10-fenantrolinium sulfat (6) dan (1)-N-etil-9-(4-metoksifenil)-7-fenil-1,10-fenantrolinium sulfat (7) dengan rendemen hasil berturut-turut 91,42 dan 86,36%. Hasil uji in vitro aktivitas antiplasmodium dari turunan senyawa 5 (senyawa 6 dan 7) terhadap P. falciparum resistan klorokuin strain FCR3 menunjukkan bahwa senyawa 7 mempunyai aktivitas antimalaria lebih tinggi dari senyawa 5 and 6. Sedangkan, hasil uji in vitro aktivitas antiplasmodium terhadap P. falciparum sensitif klorokuin strain D10 menunjukkan bahwa senyawa 6 mempunyai aktivitas antimalaria lebih tinggi dari senyawa 5 and 7.
Synthesis and in vitro antiplasmodial evaluation of 4-anilino-2-trichloromethylquinazolines
Bioorganic & Medicinal Chemistry, 2009
To identify a new safe antiplasmodial molecular scaffold, an original series of 2-trichloromethylquinazolines, functionalized in position 4 by an alkyl-or arylamino substituent, was synthesized from 4chloro-2-trichloromethylquinazoline 1, via a cheap, fast and efficient solvent-free operating procedure. Among the 40 molecules prepared, several exhibit a good profile with both a significant antiplasmodial activity on the W2 Plasmodium falciparum strain (IC 50 values: 0.4-2.2 lM) and a promising toxicological behavior regarding human cells (HepG2/W2 selectivity indexes: 40-83), compared to the antimalarial drug compounds chloroquine and doxycycline. The in vitro antitoxoplasmic and antileishmanial evaluations were conducted in parallel on the most active molecules, showing that these ones specifically display antiplasmodial properties.
European Journal of Medicinal Chemistry, 2021
The identification of a plant-like Achille's Heel relict, i.e. the apicoplast, that is essential for Plasmodium spp., the causative agent of malaria lead to an attractive drug target for new antimalarials with original mechanism of action. Although it is not photosynthetic, the apicoplast retains several anabolic pathways that are indispensable for the parasite. Based on previously identified antiplasmodial hit-molecules belonging to the 2-trichloromethylquinazoline and 3trichloromethylquinoxaline series, we report herein an antiplasmodial Structure-Activity Relationships (SAR) study at position two of the quinoxaline ring of 16 newly synthesized compounds. Evaluation of their activity toward the multi-resistant K1 Plasmodium falciparum strain and cytotoxicity on the human hepatocyte HepG2 cell line revealed a hit compound (3k) with a PfK1 EC50 value of 0.3 µM and a HepG2 CC50 value of 56.0 µM (selectivity index = 175). Moreover, hitcompound 3k was not cytotoxic on VERO or CHO cell lines and was not genotoxic in the in vitro comet assay. Activity cliffs were observed when the trichloromethyl group was replaced by CH3, CF3 or H, showing that this group played a key role in the antiplasmodial activity. Biological investigations performed to determine the target and mechanism of action of the compound 3k strongly suggest that the apicoplast is the putative target as showed by severe alteration of apicoplaste biogenesis and delayed death response. Considering that there are very few molecules that affect the Plasmodium apicoplast, our work provides, for the first time, evidence of the biological target of trichloromethylated derivatives. Key words Quinoxaline Trichloromethyl goup Plasmodium falciparum In vitro antiplasmodial activity Structure-activity relationships Apicoplast Highlights • 16 new compounds were obtained in the 2-thiophenoxy-3-trichloromethylquinoxaline series • 3k showed good and selective antiplasmodial activity and was not genotoxic • The trichloromethyl group is essential for providing the antiplasmodial activity • The hit molecule 3k showed typical anti-apicoplast activity • Size of schizonts were affected at high concentration of 3k without hepatotoxicity Graphical abstract
Antimicrobial Agents and Chemotherapy, 2007
A series of novel 10-N-substituted acridones, bearing alkyl side chains with tertiary amine groups at the terminal position, were designed, synthesized, and evaluated for the ability to enhance the potency of quinoline drugs against multidrug-resistant (MDR) Plasmodium falciparum malaria parasites. A number of acridone derivatives, with side chains bridged three or more carbon atoms apart between the ring nitrogen and terminal nitrogen, demonstrated chloroquine (CQ)-chemosensitizing activity against the MDR strain of P. falciparum (Dd2). Isobologram analysis revealed that selected candidates demonstrated significant synergy with CQ in the CQ-resistant (CQR) parasite Dd2 but only additive (or indifferent) interaction in the CQ-sensitive (CQS) D6. These acridone derivatives also enhanced the sensitivity of other quinoline antimalarials, such as desethylchloroquine (DCQ) and quinine (QN), in Dd2. The patterns of chemosensitizing effects of selected acridones on CQ and QN were similar to those of verapamil against various parasite lines with mutations encoding amino acid 76 of the P. falciparum CQ resistance transporter (PfCRT). Unlike other known chemosensitizers with recognized psychotropic effects (e.g., desipramine, imipramine, and chlorpheniramine), these novel acridone derivatives exhibited no demonstrable effect on the uptake or binding of important biogenic amine neurotransmitters. The combined results indicate that 10-N-substituted acridones present novel pharmacophores for the development of chemosensitizers against P. falciparum.