Synthesis and antimalarial activity of new haemanthamine-type derivatives

Thirty one derivatives were prepared from the natural alkaloids haemanthamine (1), haemanthidine (2) and 11-hydroxyvittatine (3). They were evaluated for their in vitro antimalarial activity against chloroquine-sensitive strains of Plasmodium falciparum and some structure-activity relationships were outlined. For haemanthamine derivatives having a methoxy group at C-3, the presence of a free hydroxyl group at C-11 is important for the activity. The double bond at C-1-C-2 plays also an important role to achieve good inhibitory activity. Compound 35 with two nicotinate groups at C-3 and at C-11 was the most active compound with a IC(50)=0.8±0.06μM.     

Synthesis and antimalarial activity of some new 1,2-dioxolane derivatives

The synthesis of 1,2-dioxolane derivatives in two different acetophenone series, as simplified models of natural coumarins is described. 2-Acetyl-3-acetoxy-4-(3-hydroperoxy-3-methylbut-1-enyl)phenyl acetate and 2-acetyl-5-acetoxy4-(3-hydroperoxy-3-methylbut-1-enyl) phenyl acetate synthons are used as precursors to these structures. In vitro antimalarial activity of the 1,2-dioxolane derivatives has been investigated.     

Synthesis and antimalarial evaluation of a series of piperazinyl flavones

A series of 27 flavonoid derivatives containing a piperazinyl chain have been synthesized and tested for their antiplasmodial activity. Diverse substitution patterns on piperazinyl and flavone moieties were examined and found to affect the activity differently. The most active compounds, which have a 2,3,4-trimethoxybenzylpiperazinyl chain attached to the flavone at the 7-phenol group, showed in vitro activity against chloroquine-sensitive (Thai) and -resistant (FcB1,K1) Plasmodium falciparum strains in the micromolar to submicromolar range. One of them was active when given orally in a Plasmodium yoelii nigeriensis infected mouse model.     

Search for new pharmacophores for antimalarial activity. Part II: Synthesis and antimalarial activity of new 6-ureido-4-anilinoquinazolines

Synthesis of new 6-ureido-4-anilinoquinazolines have been accomplished and their in vitro antimalarial activity against chloroquine-sensitive P. falciparum have been examined. Out of 64 compounds evaluated, the IC₅₀ of 16 compounds which have displayed MIC of 0.25 μg/mL were also recorded. One of the compounds (24g) had IC₅₀ value of 2.27 ng/mL which was equipotent to the standard drug chloroquine used in the bioassay. The in vivo evaluation of a few compounds among the series led to discovery of one analog (30g) displaying 40% curative activity (28 days) against mdr P. yoeilli nigeriensis at an oral dose of 100 mg/kg × 4days.     

Synthesis,antimalarial activity,and cellular toxicity of new arylpyrrolylaminoquinolines

A set of nine new arylpyrrolyl derivatives of 7-chloro-4-aminoquinoline, characterized by different substituents on the phenyl ring or different distance between the pyrrolic nitrogen and the 4-aminoquinoline, has been synthesized and tested for their activity against D-10 (CQ-S) and W-2 (CQ-R) strains of Plasmodium falciparum. All compounds exhibited activity against the CQ-S strain in the low nM range, comparable to that of chloroquine. Some of them were also highly active against the CQ-R strain and not toxic against normal cells. The antimalarial activity of this new class of compounds seems to be related to the inhibition of heme detoxification process of parasites, as in the case of chloroquine.     

Synthesis and antimalarial activity of new chloroquine analogues carrying a multifunctional linear side chain

We report the synthesis and in vitro antimalarial activity of several new 4-amino- and 4-alkoxy-7-chloroquinolines carrying a linear dibasic side chain. Many of these chloroquine analogues have submicromolar antimalarial activity versus HB3 (chloroquine sensitive) and Dd2 (chloroquine resistant strain of Plasmodium falciparum) and low resistance indices were obtained in most cases. Importantly, compounds 11–15 and 24 proved to be more potent against Dd2 than chloroquine. Branching of the side chain structure proved detrimental to the activity against the CQR strain.     

Synthesis and antiviral activity of a new series of 4-isothiazolecarbonitriles

A series of 4-isothiazolecarbonitriles was synthesized and screened for in vitro antiviral activity. The effect of various substituents on the phenyl ring, as well as the substitution of the phenyl for other aromatic and heteroaromatic rings, was examined to establish the requirements for optimum activity. The most active member of the series, 3-methylthio-5-phenyl-4-isothiazolecarbonitrile, exhibited a high level of activity against enteroviruses polio 1 and ECHO 9. Preliminary studies on its mechanism of action indicated that this compound had an effect on an early event in the replication of poliovirus type 1.     

Search for new pharmacophores for antimalarial activity. Part I: Synthesis and antimalarial activity of new 2-methyl-6-ureido-4-quinolinamides

A total of 80 new 2-methyl-6-ureido-4-quinolinamides were synthesized and evaluated for their antimalarial activity. Several analogs elicited the antimalarial effect at MIC of 0.25 mg/mL against the chlooquine-sensitive P. falciparum strain. The IC₅₀ values of the active compounds were observed to be in ng/mL range and two of the analogs have better IC₅₀ value than the standard chloroquine. In the in vivo assay against mdr CQ resistant P. yoelii N67/P. yoelii nigeriensis, however, none of the compound showed complete suppression of parasitemia on day 7. One of the compounds displayed significant antibacterial effect against several strains of bacteria and was many-fold better than the standard drug gentamicin.     

Synthesis and cytotoxic activity of a new series of topoisomerase I inhibitors

A series of structurally simple analogues of natural topopyrone C were synthesized and tested for cytotoxic and topoisomerase I inhibitory activities. The removal of the hydroxyl groups at the 5 and 9 positions resulted in an increased cytotoxic potency and ability to stabilize topoisomerase-mediated cleavage. In addition, the results suggest that some structural features, such as the pyrone ring and a polar group in position 11, are fundamental for topoisomerase I inhibitory effect. These structural requirements are also consistent with the cytotoxic activity.     

Synthesis,antimalarial activity and cytotoxic potential of new monocarbonyl analogues of curcumin

A series of novel monocarbonyl analogues of curcumin have been designed, synthesized and tested for their activity against Molt4, HeLa, PC3, DU145 and KB cancer cell lines. Six of the analogues showed potent cytotoxicity towards these cell lines with IC₅₀ values below 1 μM, which is better than doxorubicin, a US FDA approved drug. Several analogues were also found to be active against both CQ-resistant (W2 clone) and CQ-sensitive (D6) strains of Plasmodium falciparum in an in-vitro antimalarial screening. This level of activity warrants further investigation of the compounds for development as anticancer and antimalarial agents.     

Synthesis, characterization and antimalarial activity of new chromium arene-quinoline half sandwich complexes

Organometallic analogs of chloroquine (CQ) are of interest as drug candidates that may be able to overcome the widespread chloroquine resistance developed by malaria parasites. Two new chromium arene CQ-analogs: [η⁶-N-(7-chloroquinolin-4-yl)-N′-(2-dimethylamino-methylbenzyl)-ethane-1,2-diamine]tricarbonylchromium 4 and [η⁶-N-(7-chloroquinolin-4-yl)-N′-(2-dimethylaminobenzyl)-ethane-1,2-diamine]tricarbonylchromium 9 have been synthesized and characterized. In addition, X-ray crystal structures of the intermediates (η⁶-benzyldimethylamine)tricarbonylchromium 2, [η⁶-2-((dimethylamino)methyl) benzaldehyde]tricarbonylchromium 3 and p-(η⁶-dimethylaminobenzaldehyde)tricarbonyl chromium 8 are reported. Compound 4 was more active than chloroquine against both CQ-sensitive and CQ-resistant strains of Plasmodium falciparum when antimalarial activity was tested in vitro. The activity of 4 against the CQ-resistant parasite strain was twice as high as for the organic ligand alone (IC₅₀ values of 33.9 nM versus 63.1 nM).     

Synthesis and antimalarial activity of new heterocyclic hybrids based on chloroquine and thiazolidinone scaffolds

A series of new 21 chloroquine heterocyclic hybrids containing either benzylamino fragment or N-(aminoalkyl)thiazolidin-4-one moiety were synthesized and screened for their antimalarial activity against chloroquine (CQ)-sensitive 3D7 and multidrug-resistance Dd2 strains of Plasmodium falciparum. Although no compounds more active than CQ against 3D7 was found; against Dd2 strain, six compounds, four of them with benzylamino fragment, showed an excellent activity, up to 3-fold more active than CQ. Non specific cytotoxicity on J774 macrophages was observed in some compounds whereas only two of them showed liver toxicity on HepG2 cells. In addition, all active compounds inhibited the ferriprotoporphyrin IX biocrystalization process in concentrations around to CQ. In vivo preliminary results have shown that at least two compounds are as active as CQ against Plasmodium berghei ANKA.     

Synthesis of a Microcystis aeruginosa predicted metabolite with antimalarial activity

The synthesis of a Microcystis aeruginosa predicted metabolite analog of aerucyclamide B was performed. This hexacyclopeptide was obtained from three heterocyclic building blocks by a convergent macrocycle-assembly methodology. The compound exhibited good in vitro antiplasmodial activity (IC(50): 0.18 μM, K1, cholorquine resistant strain).     

Synthesis and antimalarial activity of new 1,12-bis(N,N'-acetamidinyl)dodecane derivatives

Amidoxime and O-substituted derivatives of the bis-alkylamidine 1,12-bis(N,N'-acetamidinyl)dodecane were synthesized and evaluated as in vitro and in vivo antimalarial prodrugs. The bis-O-methylsulfonylamidoxime 8 and the bis-oxadiazolone 9 derivatives show relatively potent antimalarial activity after oral administration.     

Synthesis,antimalarial and antitubercular activity of acetylenic chalcones

A series of acetylenic chalcones were evaluated for antimalarial and antitubercular activity. The antimalarial data for this series suggests that growth inhibition of the W2 strain of Plasmodium falciparum can be imparted by the introduction of a methoxy group ortho to the acetylenic group. Most compounds were more active against non-replicating than replicating cultures of Mycobacterium tuberculosis H₃₇Rv, an unusual pattern with respect to existing anti-TB agents.     

Synthesis and antimalarial activity of 6-cycloalkylvinyl substituted 1,2,4-trioxanes

6-Cycloalkylvinyl substituted 1,2,4-trioxanes 6-15 have been prepared and tested against multi-drug resistant Plasmodium yoelii in mice. The most active trioxane 11 provides 80% protection to the treated mice. Further derivatization of 11 leads to decrease in antimalarial activity.     

Synthesis of substituted indole derivatives as a new class of antimalarial agents

A series of substituted indole derivatives were synthesized and evaluated for their in vitro antimalarial activity against P. falciparum. Out of the 24 compounds synthesized six compounds have shown MIC of 1 microg/mL. These compounds are in vitro several folds more active than pyrimethamine.     

Synthesis and antimalarial activity of new 4-amino-7-chloroquinolyl amides,sulfonamides, ureas and thioureas

We report the synthesis and in vitro antimalarial activities of more than 50 7-chloro-4-aminoquinolyl-derived sulfonamides 3–8 and 11–26, ureas 19–22, thioureas 23–26, and amides 27–54. Many of the CQ analogues prepared for this study showed submicromolar antimalarial activity versus HB3 (chloroquine sensitive) and Dd2 (chloroquine resistant strains of Plasmodium falciparum) and low resistance indices were obtained in most cases. Systematic variation of the side chain length and introduction of fluorinated aliphatic and aromatic termini revealed promising leads that overcome CQ resistance. In particular, sulfonamide 3 exhibiting a short side chain with a terminal dansyl moiety combined high antiplasmodial potency with a low resistance index and showed IC₅₀s of 17.5 and 22.7 nM against HB3 and Dd2 parasites.     

Synthesis and structure-activity relationships of novel benzoxaboroles as a new class of antimalarial agents

A series of boron-containing benzoxaborole compounds was designed and synthesized for a structure-activity relationship investigation surrounding 7-(HOOCCH₂CH₂)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (1) with the goal of discovering a new antimalarial treatment. Compound 1 demonstrates the best potency (IC₅₀ = 26 nM) against Plasmodium falciparum and has good drug-like properties, with low molecular weight (206.00), low ClogP (0.86) and high water solubility (750 μg/mL at pH 7).