New Compounds Hybrids 1H‐1,2,3‐Triazole‐Quinoline Against Plasmodium falciparum

Malaria is one of the most prevalent parasitic diseases in the world. The global importance of this disease, current vector control limitations, and the absence of an effective vaccine make the use of therapeutic antimalarial drugs the main strategy to control malaria. Chloroquine is a cost‐effective antimalarial drug with a relatively robust safety profile, or therapeutic index. However, chloroquine is no longer used alone to treat patients with Plasmodium falciparum due to the emergence and spread of chloroquine‐resistant strains, which have also been reported for Plasmodium vivax. However, the activity of 1,2,3‐triazole derivatives against chloroquine‐sensitive and chloroquine‐resistant strains of P. falciparum has been reported in the literature. To enhance the anti‐P. falciparum activity of quinoline derivatives, we synthesized 11 new quinoline‐1H‐1,2,3‐triazole hybrids with different substituents in the 4‐positions of the 1H‐1,2,3‐triazole ring, which were assayed against the W2‐chloroquine‐resistant P. falciparum clone. Six compounds exhibited activity against the P. falciparum W2 clone, chloroquine‐resistant, with IC₅₀ values ranging from 1.4 to 46 μm . None of these compounds was toxic to a normal monkey kidney cell line, thus exhibiting good selectivity indexes, as high 351 for one compound ( 11 ).     

Synthesis,Docking, In Vitro and In Vivo Antimalarial Activity of Hybrid 4‐aminoquinoline–1,3,5‐triazine Derivatives Against Wild and Mutant Malaria Parasites

A new series of hybrid 4‐aminoquinoline–1,3,5‐triazine derivatives was synthesized by a four‐step reaction. Target compounds were screened for in vitro antimalarial activity against chloroquine‐sensitive (3D‐7) and chloroquine‐resistant (RKL‐2) strains of Plasmodium falciparum. Compounds exhibited, by and large, good antimalarial activity against the resistant strain, while two of them, that is 8g and 8a, displayed higher activity against both the strains of P. falciparum. Additionally, docking study was performed on both wild (1J3I.pdb) and quadruple mutant (N51I, C59R, S108 N, I164L, 3QG2.pdb) type pf‐DHFR‐TS to highlight the structural features of hybrid molecules.     

Mechanism-based design of parasite-targeted artemisinin derivatives: synthesis and antimalarial activity of new diamine containing analogues

The potent antimalarial activity of chloroquine against chloroquine-sensitive strains can be attributed, in part, to its high accumulation in the acidic environment of the heme-rich parasite food vacuole. A key component of this intraparasitic chloroquine accumulation mechanism is a weak base "ion-trapping" effect whereupon the basic drug is concentrated in the acidic food vacuole in its membrane-impermeable diprotonated form. By the incorporation of amino functionality into target artemisinin analogues, we hoped to prepare a new series of analogues that, by virtue of increased accumulation into the ferrous-rich vacuole, would display enhanced antimalarial potency. The initial part of the project focused on the preparation of piperazine-linked analogues (series 1 (7-16)). Antimalarial evaluation of these derivatives demonstrated potent activity versus both chloroquine-sensitive and chloroquine-resistant parasites. On the basis of these observations, we then set about preparing a series of C-10 carba-linked amino derivatives. Optimization of the key synthetic step using a newly developed coupling protocol provided a key intermediate, allyldeoxoartemisinin (17) in 90% yield. Further elaboration, in three steps, provided nine target C-10 carba analogues (series 2 (21-29)) in good overall yields. Antimalarial assessment demonstrated that these compounds were 4-fold more potent than artemisinin and about twice as active as artemether in vitro versus chloroquine-resistant parasites. On the basis of the products obtained from biomimetic Fe(II) degradation of the C-10 carba analogue (23), we propose that these analogues may have a mode of action subtly different from that of the parent drug artemisinin (series 1 (7-16)) and other C-10 ether derivatives such as artemether. Preliminary in vivo testing by the WHO demonstrated that four of these compounds are active orally at doses of less than 10 mg/kg. Since these analogues are available as water-soluble salts and cannot form dihydroartemisinin by P450-catalyzed oxidation, they represent useful leads that might prove to be superior to the currently used derivatives, artemether and artesunate.     

Interaction of berbamine and chloroquine or artemisinin against chloroquine-sensitive and -resistant plasmodium falciparum in vitro

Antimalarial activity of berbamine (BB), alone or in combination with chloroquine (CQ) or artemisinin (qinghaosu, QHS), was studied using CQ-sensitive and -resistant strains of Plasmodium falciparum in vitro. BB was found to have antimalarial effects with IC₅₀ values of 603 and 359 nM, respectively, for the drug-sensitive and -resistant strains of P. falciparum, indicating that BB exhibited some selective antimalarial activity against the drug-resistant parasite. Its antimalarial efficacy and selectivity appeared to be less than that of tetrandrine (TT), however, when BB was combined with CQ, an antagonistic interaction was found against the CQ-sensitive parasite, while a potentiating antimalarial action was observed with the CQ-resistant parasite. When BB was tested in combination with QHS, a complex interaction was found—one was additive for the CQ-sensitive parasite and the other was potentiating for the CQ-resistant parasite. The above data suggested that the BB combination with either CQ or QHS is a promising candidate for an antimalarial remedy to treat at least CQ-resistant falciparum parasites which cause malaria. © 1993 wiley-Liss, Inc.     

Antimalarial activity of new water-soluble dihydroartemisinin derivatives. 2. Stereospecificity of the ether side chain

A new series of hydrolytically stable and water-soluble dihydroartemisinin derivatives with optically active side chains was prepared as potential antimalarial agents. This was an effort to prepare compounds with activity superior to that of artelinic acid and to examine the impact of the stereospecificity of the introduced alkyl side chain on biological properties. The ester derivatives (6a-d) possess superior in vitro activity to artemisinin, artemether, and arteether against two strains of Plasmodium falciparum (D-6 and W-2); however, conversion of the esters to their corresponding acids drastically reduces their antimalarial activity. None of the new acids possess in vitro antimalarial activity superior to that of artelinic acid. Although there appears to be limited stereospecificity for antimalarial activity among the acids (7a-d) tested, significant differences in antimalarial activity was seen among the esters.     

Facile synthesis and in-vitro antimalarial activity of novel α-hydroxy hydrazonates

A series of previously unreported α‐hydroxy hydrazonates were synthesized and tested for their antimalarial properties. Structure optimization of the antiplasmodially active α‐hydroxy hydrazonate III furnished derivatives with strong in‐vitro antimalarial activity against 3D7 strains of Plasmodium falciparum with IC₅₀ values lower than 2.0 µM.     

Design,synthesis, and antiprotozoal evaluation of new 2,9‐bis[(substituted‐aminomethyl)phenyl]‐1,10‐phenanthroline derivatives

A series of new 2,9‐bis[(substituted‐aminomethyl)phenyl]‐1,10‐phenanthroline derivatives was synthesized, and the compounds were screened in vitro against three protozoan parasites (Plasmodium falciparum, Leishmania donovani, and Trypanosoma brucei brucei). Biological results showed antiparasitic activity with IC₅₀ values in the μm range. The in vitro cytotoxicity of these molecules was assessed by incubation with human HepG2 cells; for some derivatives, cytotoxicity was observed at significantly higher concentrations than antiparasitic activity. The 2,9‐bis[(substituted‐aminomethyl)phenyl]‐1,10‐phenanthroline 1h was identified as the most potent antimalarial candidate with ratios of cytotoxic‐to‐antiparasitic activities of 107 and 39 against a chloroquine‐sensitive and a chloroquine‐resistant strain of P. falciparum, respectively. As the telomeres of the parasite P. falciparum are the likely target of this compound, we investigated stabilization of the Plasmodium telomeric G‐quadruplexes by our phenanthroline derivatives through a FRET melting assay. The ligands 1f and 1m were noticed to be more specific for FPf8T with higher stabilization for FPf8T than for the human F21T sequence.     

Design,synthesis and in vitro antiplasmodial activity of some bisquinolines against chloroquine‐resistant strain

A series of novel bisquinoline compounds comprising N¹‐(7‐chloroquinolin‐4‐yl) ethane‐1,2‐diamine and 7‐chloro‐N‐(2‐(piperazin‐1‐yl)ethyl)quinolin‐4‐amine connected with 7‐chloro‐4‐aminoquinoline containing various amino acids is described. We have bio‐evaluated the compounds against both chloroquine‐sensitive (3D7) and chloroquine‐resistant (K1) strains of Plasmodium falciparum in vitro. Among the series, compounds 4 and 7 exhibited 1.8‐ and 10.6‐fold superior activity as compared to chloroquine (CQ; IC₅₀ = 0.255 ± 0.049 μm ) against the K1 strain with IC₅₀ values 0.137 ± 0.014 and 0.026 ± 0.007 μm , respectively. Furthermore, compound 7 also displayed promising activity against the 3D7 strain (IC₅₀ = 0.024 ± 0.003 μm ) of P. falciparum when compared to CQ. All the compounds in the series displayed resistance factor between 0.57 and 4.71 as against 51 for CQ. These results suggest that bisquinolines can be explored for further development as new antimalarial agents active against chloroquine‐resistant P. falciparum.     

Synthesis and antimalarial activity evaluation of some isoquine analogues

The worldwide diffusion of resistance in malaria parasite, especially the Plasmodium falciparum, towards currently available drugs has become a major health and development challenges to human society. Isoquine, an isomeric analogue of amodiaquine, has been reported recently as a second generation lead compound for development of cost-effective and potentially safer alternative to amodiaquine which cause adverse effects including agranulocytosis and liver damage. In this study, a series of seven analogues of isoquine have been synthesized and subjected to in vitro antimalarial activity screening against the chloroquine sensitive 3D7 strain of Plasmodium falciparum. A simple two-step Mannich reaction was used to synthesize the compounds. All the seven compounds possessed little to moderate antimalarial activity. However, the analogues with aliphatic alcoholic amino group side chain having promising activity than the compounds with substituted aromatic ring side chain and compounds substituted with urea while analogues with heterocyclic ring side chain exhibits moderate antimalarial activity.     

The therapeutic potential of semi-synthetic artemisinin and synthetic endoperoxide antimalarial agents

Artemisinin derivatives such as artesunate, dihydroartemisinin and artemether are playing an increasing role in the treatment of drug-resistant malaria. They are the most potent antimalarials available, rapidly killing all asexual stages of the parasite Plasmodium falciparum. This review highlights the recent developments in the area of improved second-generation semi-synthetic artemisinin derivatives and fully synthetic antimalarial endoperoxide drugs. In pursuit of synthetic analogues of the artemisinins, one of the major challenges for chemists in this area has been the non-trivial development of techniques for the introduction of the peroxide bridge into candidate drugs. Although chemical research has enabled chemists to incorporate the endoperoxide ‘warhead’ into synthetic analogues of artemisinin, significant drawbacks with many candidates have included comparatively poor antimalarial activity, non-stereoselective syntheses and chemical approaches that are not readily amenable to scale up. However, very recent progress with synthetic 1,2,4-trioxolanes provides a new benchmark for future medicinal chemistry efforts in this area.     

4‐Aminoquinoline‐Triazine‐Based Hybrids with Improved In Vitro Antimalarial Activity Against CQ‐Sensitive and CQ‐Resistant Strains of Plasmodium falciparum

A systematic chemical modification in the triazine moiety covalently attached via suitable linkers to 4‐amino‐7‐chloroquinolines yielded a series of new 7‐chloro‐4‐aminoquinoline‐triazine hybrids exhibiting high in vitro activity against W2 (chloroquine‐resistant) and D6 (chloroquine‐sensitive) strains of Plasmodium falciparum without any toxicity against mammalian cell lines (Vero, LLC‐PK11, HepG2). Many of the compounds ( 6, 8, 10, 11, 13, 14, 16, 27, 29 and 33 ) showed excellent potency against chloroquine sensitive and resistant strains. In particular, compounds 6, 8 , 14 , 16 and 29 were found to be significantly more active than chloroquine against the chloroquine‐resistant strains (W2 clone) of P. falciparum.     

Synthesis,in vitro antiplasmodial and antiproliferative activities of a series of quinoline–ferrocene hybrids

Series of quinoline–ferrocene hybrids containing various linkers were synthesized and evaluated for antimalarial and anticancer activities as well as cytotoxicity. The hybrids with rigid linkers were found to be inactive, while those with flexible spacers showed activity against both the D10 and Dd2 strains of Plasmodium falciparum, and demonstrated a good selectivity towards these parasitic cells in comparison with emetine. The hybrid 16, featuring 3-aminopropyl methylamine linker, was the most antimalarial active compound, exhibiting a significantly better potency than chloroquine against the Dd2 strain (IC₅₀ = 0.008 vs. 0.148 μM; 19-fold), and was also found to be significantly more active than the equimolar chloroquine–ferrocene combination (IC₅₀ = 3.7 vs. 41 ng/ml, tenfold) against the Dd2 strain. Anticancer activity screening showed that all the antimalarial active hybrids also exhibited potent cytostatic (GI₅₀ = 0.6–3.3 μM) and had good cytotoxic effects (LC₅₀ = 6–8 μM) against all three cancer cell lines. The hybrid 11 possessing 1,4-butanediamine linker was distinctively the most antiproliferative of all. It was found to be more cytostatic (GI₅₀: 0.7 vs. 5.9 μM, eightfold) and (LC₅₀: 6.4 vs. 92.6 μM, 14-fold) more cytotoxic than etoposide against the TK10 (renal) cell line.     

Antimalarial Effect of 3‐Methoxy‐1,2‐Dioxetanes on the Erythrocytic Cycle of Plasmodium falciparum

The antimalarial activity of peroxides most likely originates from their interaction with iron(II) species located inside the malaria parasite, which forms destructive radical species through a Fenton‐like mechanism. This article reports the first evaluation of the in vitro antimalarial activity of three peroxides of the class 1,2‐dioxetanes against Plasmodium falciparum; the results reveal that the studied 3‐methoxy‐1,2‐dioxetanes display significant antimalarial activity, at a similar level as artemisinin and also that their reactivity toward iron(II) correlate linearly with their antimalarial activity.     

青蒿素类似物的研究——Ⅰ、还原青蒿素的醚类、羧酸酯类及碳酸酯类衍生物的合成

青蒿素是当前治疗抗恶性疟疾的首选药物。为克服它的近期复燃率高的缺点,我们以还原青蒿素为中间体,在酸或碱的催化下与各种醇、羧酸酐或酰氯、氯甲酸酯反应,合成了它的醚类,羧酸酯类和碳酸酯类衍生物47个。经鼠疟(P.berghei)抗氯喹原虫株筛选,发现其中大多数化合物的抗疟效果超过青蒿素;以SD₉₀)作比较标准,超过青蒿素十倍左右的化合物有12个。     

Design and Synthesis of a New Class of 4‐Aminoquinolinyl‐ and 9‐Anilinoacridinyl Schiff Base Hydrazones as Potent Antimalarial Agents

A series of novel 4‐aminoquinolinyl and 9‐anilinoacridinyl Schiff base hydrazones have been synthesized and evaluated for their antimalarial activity. All compounds were evaluated in vitro for their antimalarial activity against chloroquine‐sensitive strain 3D7 and the chloroquine‐resistant K1 strain of Plasmodium falciparum and for cytotoxicity toward Vero cells. Compounds 17 , 20 , and 21 displayed good activity against the 3D7 strain with IC₅₀ values ranging from 19.69 to 25.38 nm . Moreover, compounds 16 , 17 , 21 , 24 , 32, and 33 exhibited excellent activities (21.64–54.26 nm ) against K1 strain and several compounds displayed β‐hematin inhibitory activity, suggesting that they act on the heme crystallization process such as CQ. Compounds were also found to be non‐toxic with good selectivity index.     

Synthesis of thiazolyl hydrazonothiazolamines and 1,3,4‐thiadiazinyl hydrazonothiazolamines as a class of antimalarial agents

Novel thiazolyl hydrazonothiazolamines and 1,3,4‐thiadiazinyl hydrazonothiazolamines were synthesized by a facile one‐pot multicomponent approach by the reaction of 2‐amino‐4‐methyl‐5‐acetylthiazole, thiosemicarbazide or thiocarbohydrazide and phenacyl bromides or 3‐(2‐bromoacetyl)‐2H‐chromen‐2‐ones in acetic acid with good to excellent yields. These new compounds were screened in vitro for their antimalarial activity; among them, four compounds, 4h, 4i, 4k, 4l , showed moderate activity with half‐maximal inhibitory concentration (IC₅₀) values of 3.2, 2.7, 2.7, and 2.8 and 3.2, 3.2, 3.1, and 3.5 μM against chloroquine‐sensitive and ‐resistant strains of Plasmodium falciparum, respectively. Compound 4l inhibited the ring stage growth of P. falciparum 3D7 at an IC₉₀ concentration of 12.5 µM in a stage‐specific assay method, where the culture is incubated with specific stages of P. falciparum for 12 hr, and no activity was found against the trophozoite and schizont stages, confirming that 4l may have potent action against the ring stage of P. falciparum.     

Preparation of chemically robust new artemisinin derivatives

The resurgence of malaria, largely through emergence of drug-resistant strains of the malaria parasite, Plasmodium falciparum, has in recent times substantially increased public and private focus on the development of new treatments for the disease. However, in the absence of any vaccine, major reliance continues to be placed on chemotherapy involving both traditional, largely quinoline-based, antimalarial drugs and the newer class of antimalarial drug based on artemisinin, the remarkable peroxidic sesquiterpene isolated by the Chinese in 1972. Derivatives of this compound, artesunate and artemether, are now used in routine therapy in conjunction with a longer half-life quinoline or related antimalarial. However, problems of instability and neurotoxicity associated with the current artemisinin derivatives has resulted in a vigorous search for new, more stable derivatives with better pharmacological profiles. The Centre Nationale de la Recherche Scientifique patent describes a class of relatively readily accessible new artemisinin derivatives, which in incorporating the trifluoromethyl group, appear to be more stable than the current derivatives.     

Novel, potent, semisynthetic antimalarial carba analogues of the first-generation 1,2,4-trioxane artemether

Ten novel, second-generation, fluorinated ether and ester analogues of the potent first-generation analogues artemether (4a) and arteether (4b) have been designed and synthesized. All of the compounds demonstrate high antimalarial potency in vitro against the chloroquine-sensitive HB3 and -resistant K1 strains of Plasmodium falciparum. The most potent derivative 8 was 15 times more potent than artemisinin (2) against the HB3 strain of P. falciparum. In vivo, versus Plasmodium berghei in the mouse, selected derivatives were generally less potent than dihydroartemisinin with ED(50) values of between 5 and 8 mg/kg. On the basis of the products obtained from the in vitro biomimetic Fe(II)-mediated decomposition of 8, the radical mediator of biological activity of this series may be different from that of the parent drug, artemisinin (2).     

Overcoming drug resistance to heme-targeted antimalarials by systematic side chain variation of 7-chloro-4-aminoquinolines

Systematic variation of the branching and basicity of the side chain of chloroquine yielded a series of new 7-chloro-4-aminoquinoline derivatives exhibiting high in vitro activity against four different strains of P. falciparum. Many of the compounds tested showed excellent potency against chloroquine sensitive and resistant strains. In particular 4b, 5a, 5b, 5d, 17a, and 17b were found to be significantly more potent than chloroquine against the resistant strains Dd2 and FCB.     

Synthesis, cytotoxicity and antimalarial activity of ferrocenyl amides of 4-aminoquinolines

Series of 4-aminoquinolines bearing an amino side chain linked to the ferrocene moiety through an amide bond were synthesized and evaluated for their antimalarial activity against both chloroquine-sensitive (D10, CQ-S) and chloroquine-resistant (Dd2, CQ-R) strains of Plasmodium falciparum. They were also tested for cytotoxicity against Chinese Hamster Ovarian (CHO) cells. Amide 12 featuring propyl side chain linked to the ferrocene ring was the most active of all tested compounds. With an IC50 value of 0.08 microg/mL, this amide showed 1.5-fold higher activity than chloroquine diphosphate (IC50 = 0.12 microg/mL) against the resistant strain, with a selectivity index of 550 indicating its high selectivity towards the parasite. Derivatives which were equipotent against both strains also showed up to ten-fold increase in activity compared to primaquine.