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,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.     

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 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.     

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.     

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.     

Potent antimalarial activity of newly synthesized substituted chalcone analogs in vitro

Abstract   Several new chalcone analogues were synthesized and evaluated as inhibitors of malaria parasite. Inhibitory activity was determined in vitro against a chloroquine-sensitive Plasmodium falciparum strain of parasites. The compound 3-(4-methoxyphenyl)-1-(4-pyrrol-1-yl-phenyl)prop-2-en-1-one was found to be the most active with 50% inhibition concentration (IC₅₀) of 1.61 μg/ml. This inhibitory concentration is comparable to a prototype phytochemical chalcone, licochalcone A, with an IC₅₀ of 1.43 μg/ml. The present study suggests that small, lipophilic nitrogen heterocyclic ring A together with small hydrophobic functionality at ring B can enhance antimalarial activity. These results suggest that chalcones are a class of compounds that provides an option of developing inexpensive, synthetic therapeutic antimalarial agents in the future. Graphical Abstract  Claisen-Schmidt condensation method was employed to synthesize various substituted chalcones. Among all, 3-(4-Methoxyphenyl)-1-(4-pyrrol-1-yl-phenyl)prop-2-en-1-one was found to be most effective with IC₅₀ value of 1.6 μg/ml in vitro against chloroquine sensitive strain (3D7) of Plasmodium falciparum.      

Novel approaches in antimalarial drug discovery

Introduction: The development of new antimalarial drugs remains of the utmost importance, since Plasmodium falciparum has developed resistance against nearly all chemotherapeutics in clinical use. In an effort to contain the resistance of P. falciparum against artemisinins and to further eradication efforts, studies are ongoing to identify novel and more efficacious approaches to develop antimalarials.

Areas covered: The authors review the classical and new approaches to antimalarial drug discovery, with a special emphasis on the various stages of the parasite's life cycle and the different Plasmodium species. The authors discuss the methodologies and strategies for early efficacy testing that aim to narrow down the portfolio of promising compounds.

Expert opinion: The increased efforts in the discovery and development of new antimalarial compounds have led to the recognition of new promising hits. However, there is still major roadblock of selecting the most promising compounds and then further testing them in early clinical trials, especially in the current restricted economy. Controlled human malaria infection has much potential for speeding-up the early development process of many drug candidates including those which target the pre-erythrocytic stages.     

Synthesis and antimalarial evaluation of novel pyridine quinoline hybrids

Abstract  Synthesis and evaluation of the antimalarial activity of new pyridine quinoline hybrid molecules against a chloroquine-susceptible strain of Plasmodium falciparum and as inhibitors of β-hematin formation are described. Two novel pyridine quinoline hybrid molecules and one bisquinoline molecule were synthesized and purified by column chromatography and evaluated for antimalarial and haem polymerization inhibition (HPIA) activities. The molecules were found to be very good haem polymerization inhibitors but showed poor antimalarial activity. This was attributed to their low vacuole accumulation ratio (VAR) in comparison to chloroquine. These molecules can be used as templates for designing new antimalarials targeting haem detoxification pathway of malaria parasite. Graphical Abstract   Synthesis and antimalarial evaluation of novel pyridine quinoline hybrids B.N Acharya, D. Thavaselvam^# and M.P Kaushik^* Discovery Centre, Process Technology Development Division Defence R & D Establishment, Jhansi Road, Gwalior-474002 (MP) INDIA ^#Division of Microbiology, Defence Research and Development Establishment,Gwalior-474002, India Synthesis and evaluation of antimalarial activity of new pyridine–quinoline hybrid molecules against a chloroquine-susceptible strain of Plasmodium falciparum and as inhibitors of β-hematin formation are described.     

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 ).     

In silico three-dimensional pharmacophores for aiding the discovery of the Pfmrk (Plasmodium cyclin-dependent protein kinases) specific inhibitors for the therapeutic treatment of malaria

The resurgence of malaria and lack of effective antimalarial drugs affect millions of people worldwide every year, causing several million deaths. With the emergence of structure-based drug design methodologies, a major thrust in drug discovery efforts has shifted towards targeting specific proteins in parasites that are involved in their metabolic pathways. Although cyclin-dependent kinases (CDKs), due to their direct role in cell cycle regulations, have been targeted for the development of cancer therapeutics, CDKs for Plasmodium falciparum have only been recently identified to be attractive for the discovery of antimalarials. One of the plasmodium CDK targets is Pfmrk. Being a putative homolog of Cdk7 and, thus, having the possibility of dual functions, both in cell cycle control and gene expression within the parasite, pfrmk has become an interesting antimalarial chemotherapeutic target. This review discusses how in silico methodologies, without the knowledge of the X-ray crystallographic structure of Pfmrk, particularly based on the development of pharmacophores on known inhibitors can aid the discovery and design of Pfmrk-specific inhibitors through virtual screening of compound databases and provides insights into the understanding of the mechanism of binding in the active site of this enzyme.     

7‐Chloroquinoline–isatin Conjugates: Antimalarial,Antitubercular, and Cytotoxic Evaluation

A series of twenty piperazine‐tethered 7‐chloroquinoline–isatin hybrids have been synthesized via either direct nucleophilic substitution or Cu(Ι)Cl‐mediated Mannich reaction. These new conjugates were evaluated for their antimalarial and antitubercular efficacy against a chloroquine‐resistant strain of Plasmodium falciparum and Mycobacterium tuberculosis, respectively, while the cytotoxic profiles were evaluated against 3T6 cell line, a permanent mouse embryonic fibroblast cell line. The most potent of the test compound with IC₅₀ of 0.22 μm against W2 strain of P. falciparum and 31.62 μm against the embryonic fibroblast cell line (cytotoxicity) displayed a high selective index of 143.73.     

Synthesis and antimalarial activity of ethylene glycol oligomeric ethers of artemisinin

Objectives The aim of this study was to synthesize a series of ethylene glycol ether derivatives of the antimalarial drug artemisinin, determine their values for selected physicochemical properties and evaluate their antimalarial activity in vitro against Plasmodium falciparum strains. Methods The ethers were synthesized in a one‐step process by coupling ethylene glycol moieties of various chain lengths to carbon C‐10 of artemisinin. The aqueous solubility and log D values were determined in phosphate buffered saline (pH 7.4). The derivatives were screened for antimalarial activity alongside artemether and chloroquine against chloroquine‐sensitive (D10) and moderately chloroquine‐resistant (Dd2) strains of P. falciparum. Key findings The aqueous solubility within each series increased as the ethylene glycol chain lengthened. The IC50 values revealed that all the derivatives were active against both D10 and Dd2 strains. All were less potent than artemether irrespective of the strain. However, they proved to be more potent than chloroquine against the resistant strain. Compound 8 , featuring three ethylene oxide units, was the most active of all the synthesized ethers. Conclusions The conjugation of dihydroartemisinin to ethylene glycol units of various chain lengths through etheral linkage led to water‐soluble derivatives. The strategy did not result in an increase of antimalarial activity compared with artemether. It is nevertheless a promising approach to further investigate and synthesize water‐soluble derivatives of artemisinin that may be more active than artemether by increasing the ethylene glycol chain length.     

Antimalarial activity of Gomphostemma crinitum leaf extracts

Abstract  Antimalarial efficacy of Gomphostemma crinitum leaf extracts were studied in vitro against the chloroquine-sensitive MRC-02 strain of Plasmodium falciparum. The CHCl₃ extract (IC₅₀ 37.28 μg/mL) was found to be better than the aqueous extract (IC₅₀ 111.4 μg/mL). The major compound present in CHCl₃ extract was coded as GC-7 (12,17-diacetoxy, 15-hydroxy, 2-oxo, 3, 13 E (14)-diene clerodane). Seasonal variation of GC-7 was studied and correlated to the antimalarial efficacy of the crude extracts of leaves collected in different months. GC-7 was found to be the only regular compound present in G. crinitum leaves throughout the year. A good correlation between antimalarial efficacy (IC₅₀ 9.3 μg/mL) and concentration of GC-7 in crude extracts was observed. The mode of action of GC-7 was found to be different from that of chloroquine. Graphical Abstract  Antimalarial activity of Gomphostemma crinitum leaf extracts B.N Acharya, Deepika Saraswat and M.P Kaushik^* Discovery Centre, Process Technology Development Division Defence R & D Establishment, Jhansi Road, Gwalior-474002 (MP) INDIA ^#Entomology division, Defence Research and Development Establishment,Gwalior-474002, India Antimalarial activity of chloroform extract of G. crinitum leaves and an isolated compound GC-7 (12,17-diacetoxy,15-hydroxy,2-oxo,3,13 E (14)-diene clerodane) against a chloroquine susceptible strain of Plasmodium falciparum is described.     

Antiplasmodial activity of New Caledonia and Vanuatu traditional medicines

Context: With the emergence of strains multiresistant to antimalarial drugs, the search for new active molecules remains a priority. Ethnopharmacology appears to be a good method of selection in such investigations.

Objective: The aim of this research work is to select plants used in Melanesian traditional medicine, in New Caledonia and Vanuatu, which should be a promising source for the isolation of new antimalarial drugs.

Materials and methods: Forty-seven plant extracts belonging to 12 families, traditionally used by the Melanesian people or belonging to an antimalarial known genus, were screened in vitro for antimalarial activity on Plasmodium falciparum chloroquine (CQ)-resistant (FcB1) and CQ-sensitive (HB3) strains. They were also tested for their inhibitory effects on a protein kinase (Pfnek) and their cytotoxicity on human breast adenocarcinoma (MCF7) cells.

Results: Among all extracts, four displayed strong in vitro activities against P. falciparum: Gardenia urvillei Montrouzier, Scleria polycarpa Boeckeler, Terminalia catappa L. and Acronychia laevis J.R. & J.G. Forster, the latter being also toxic on MCF7 cells. Except for the extracts of S. polycarpa, all others that were active on P. falciparum, also possess an inhibitory effect on Pfnek.

Discussion and conclusion: These results confirm that ethnopharmacology is an excellent approach for such investigations. The two countries considered clearly present advantages in the field. Indeed, local populations keep their traditional knowledge alive, and their flora is exceptionally rich. In New Caledonia, the high endemicity rate (74%) ranks the island as one of the world’s biodiversity hotspots. As a consequence, chances to discover new active natural compounds are also high.     

Two new bisindole alkaloids from Tabernaemontana macrocarpa Jack

Two new bisindole alkaloids, bisnaecarpamines A (1) and B (2), possessing a vobasine-sarpagine type skeleton were isolated from the bark of Tabernaemontana macrocarpa Jack. Their structures were elucidated by extensive spectroscopic methods and chemical correlation. The absolute configurations of compounds 1 and 2 were established using TDDFT-ECD calculation of the selected isomers. Bisnaecarpamine A exhibited potent antimalarial activity against Plasmodium falciparum 3D7 strain with IC₅₀ value of 28.8 µM.

Graphic abstract

     

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.     

Amide Tethered 4-Aminoquinoline-naphthalimide Hybrids: A New Class of Possible Dual Function Antiplasmodials

A series of amide tethered 4-aminoquinoline-naphthalimide hybrids has been synthesized to assess their in vitro antiplasmodial potential against chloroquine-susceptible (3D7) and chloroquine-resistant (W2) strains of Plasmodium falciparum. The most active and noncytotoxic compound had an IC₅₀ value of 0.07 μM against W2 strain and was more active than standard antimalarial drugs, including chloroquine, desethylamodiaquine, and quinine, particularly for drug resistant malaria. The promising scaffold, when subjected to heme binding and molecular modeling studies, was identified as a possible potent inhibitor of hemozoin formation and P. falciparum chloroquine resistance transporter (PfCRT), respectively, and, therefore, could act as a dual function antiplasmodial.     

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.     

Novel 4-Aminoquinoline-Pyrimidine Based Hybrids with Improved in Vitro and in Vivo Antimalarial Activity

相似文献