Antiplasmodial and antitrypanosomal activity of bicyclic amides and esters of dialkylamino acids

Several bicyclic amides and esters of dialkylamino acids were prepared. Their activities against a multiresistant strain of Plasmodium falciparum and against Trypanosoma brucei rhodesiense (STIB 900) were examined. Structure–activity relationships were discussed. Particularly the ester compounds showed good antiplasmodial and antitrypanosomal activity and a single compound was tested in vivo against Plasmodium berghei.     

Synthesis and in vitro antiprotozoal activities of 5-phenyliminobenzo[a]phenoxazine derivatives

A series of 5-phenyliminobenzo[a]phenoxazine derivatives were synthesized. The in vitro antiprotozoal activities were evaluated against Plasmodium falciparum K1, Trypanosoma cruzi, Leishmania donovani and Trypanosoma brucei rhodesiense. N,N-Diethyl-5-((4-methoxyphenyl)imino)-5H-benzo[a]phenoxazin-9-amine shows IC(50)=0.040 μmol L(-1) with a selective index of 1425 against Plasmodium falciparum K1.     

Synthesis of Carbocyclic 2-Substituted Adenine Nucleoside and Related Analogs

2-Iodonoraristeromycin, 2-iodoaristeromycin and related analogs were synthesized to investigate their inhibitory activities against human and Plasmodium falciparum S-adenosyl-L-homocysteine hydrolases.     

Synthesis of carbocyclic 2-substituted adenine nucleoside and related analogs

2-Iodonoraristeromycin, 2-iodoaristeromycin and related analogs were synthesized to investigate their inhibitory activities against human and Plasmodium falciparum S-adenosyl-L-homocysteine hydrolases.     

Antiplasmodial activities of sesquiterpene lactones from Eupatorium semialatum

Eupatorium semialatum, Plasmodium falciparum, Sesquiterpene Lactones Eupatorium semialatum is a member of the Asteraceae, which occurs in Guatemala. Previously, we reported the occurrence of sesquiterpene lactones of the eudesmanolide type as main constituents in the leaves. This paper deals with the isolation and identification of the first guaianolide found in E. semialatum. Since this plant is used against malaria and other diseases in the Guatemalan folk medicine, the main sesquiterpene lactones were tested for their activities against Plasmodium falciparum in vitro.     

Synthesis, antimalarial, antileishmanial, antimicrobial, cytotoxicity, and methemoglobin (MetHB) formation activities of new 8-quinolinamines

We report the synthesis, in vitro antiprotozoal (against Plasmodium and Leishmania), antimicrobial, cytotoxicity (Vero and MetHb-producing properties), and in vivo antimalarial activities of two series of 8-quinolinamines. N1-{4-[2-(tert-Butyl)-6-methoxy-8-quinolylamino]pentyl}-(2S/2R)-2-aminosubstitutedamides (21-33) and N1-[4-(4-ethyl-6-methoxy-5-pentyloxy-8-quinolylamino)pentyl]-(2S/2R)-2-aminosubstitutedamides (51-63) were synthesized in six steps from 6-methoxy-8-nitroquinoline and 4-methoxy-2-nitro-5-pentyloxyaniline, respectively. Several analogs displayed promising antimalarial activity in vitro against Plasmodium falciparum D6 (chloroquine-sensitive) and W2 (chloroquine-resistant) clones with high selectivity indices versus mammalian cells. The most promising analogs (21-24) also displayed potent antimalarial activity in vivo in a Plasmodium berghei-infected mouse model. Most interestingly, many analogs exhibited promising in vitro antileishmanial activity against Leishmania donovani promastigotes, and antimicrobial activities against a panel of pathogenic bacteria and fungi. Several analogs, notably 21-24, 26-32, and 60, showed less MetHb formation compared to primaquine indicating the potential of these compounds in 8-quinolinamine-based antimalarial drug development.     

Antimalarial activities of (+)-deoxoartemisitene and its novel C-11, 13 derivatives

(+)-Deoxoartemisitene and its C-11, 13 derivatives were synthesized from artemisinic acid via a short and regiospecific process and several derivatives show 10-20 times more in vitro antimalarial activities against Plasmodium falciparum than artemisinin.     

Structure and antimalarial activity of adducts of 11-azaartemisinin with conjugated terminal acetylenes

Several N-substituted 11-azaartemisinins were prepared from 11-azaartemisinin in high yield by the DMAP catalyzed addition of terminal acetylenes conjugated with electron-withdrawing groups. Their antimalarial activities against two drug-resistant strains of Plasmodium falciparum were determined.     

Biological evaluation of substituted quinolines

Several quinolines were synthesized and evaluated in vitro against several parasites (Trypanosoma brucei, T. cruzi, Leishmania infantum, L. amazonensis, Plasmodium falciparum). Then, they were evaluated in vitro (at 10 microM), against HTLV-1 transformed cells. A few of them displayed interesting activities, comparable to the reference drugs.     

Dialkylaminoalkyl derivatives of bicyclic compounds with antiplasmodial activity

Dialkylaminoalkyl derivatives of 2-azabicyclo[3.2.2]nonanes and of bicyclo[2.2.2]octanes were prepared and their activities determined in vitro against the multiresistant K₁ strain of Plasmodium falciparum. Several of the new compounds exhibited very promising antiplasmodial activity and selectivity. The results were compared to those of formerly synthesized analogues and of drugs in use. Structure–activity relationships were detected. Some of the more potent compounds were tested in vivo against Plasmodium berghei showing weak to moderate activity. A single compound was able to increase the mean survival days of infected mice.     

Synthesis of 4'-modified noraristeromycins to clarify the effect of the 4'-hydroxyl groups for inhibitory activity against S-adenosyl-L-homocysteine hydrolase

4'-Modified noraristeromycin (NAM) analogs, 4'-sulfo-, 4'-sulfamoy, 4'-azido and 4'-amino-NAM, were systematically synthesized. The inhibitory activities of these analogs and related compounds against Plasmodium falciparum and human S-adenosyl-L-homocysteine hydrolase were investigated.     

Additional interaction of allophenylnorstatine-containing tripeptidomimetics with malarial aspartic protease plasmepsin II

Based on a highly potent allophenylnorstatine-containing inhibitor, KNI-10006, against the plasmepsins of Plasmodium falciparum, we synthesized a series of tripeptide-type compounds with various N-terminal moieties and evaluated their inhibitory activities against plasmepsin II. Certain phenylacetyl derivatives exhibited extremely high affinity with K(i) values of less than 0.1n M suggesting successful hydrophobic interactions.     

Synthesis of novel thiourea,thiazolidinedione and thioparabanic acid derivatives of 4-aminoquinoline as potent antimalarials

In search of new 4-aminoquinolines which are not recognized by CQR mechanism, thiourea, thiazolidinedione and thioparabanic acid derivatives of 4-aminoquinoline were synthesized and screened for their antimalarial activities. Thiourea derivative 3 found to be the most active against CQ sensitive strain 3D7 of Plasmodium falciparum in an in vitro model with an IC₅₀ of 6.07 ng/mL and also showed an in vivo suppression of 99.27% on day 4 against CQ resistant strain N-67 of Plasmodium yoelii.     

A small library of trisubstituted pyrimidines as antimalarial and antitubercular agents

A small library of 20 trisubstituted pyrimidines were synthesized and evaluated for their in vitro antimalarial and antitubercular activities. Out of the total screened compounds, 16 compounds have shown in vitro antimalarial activity against Plasmodium falciparum in the range of 0.25-2microg/mL and 8 compounds have shown antitubercular activity against Mycobacterium tuberculosis H(37)Ra, at a concentration of 12.5microg/mL.     

Antiprotozoal activities of new bis-chlorophenyl derivatives of bicyclic octanes and aza-nonanes

The in vitro activity of newly synthesized bis-(chlorophenyl)-azabicyclo[3.2.2]nonanes and bis-(chlorophenyl)-bicyclo[2.2.2]octanes against Plasmodium falciparum K(1) (resistant to chloroquine and pyrimethamine) and Trypanosoma brucei rhodesiense was investigated. Especially the bis-(chlorophenyl)-azabicyclo[3.2.2]nonanes exhibit promising antitrypanosomal activity and were tested in vivo against Trypanosoma brucei brucei featuring moderate activities.     

Synthesis of 3′-Amino-3′-deoxyadenosine Derivatives as Potential Drugs for the Treatment of Malaria

Abstract

A series of 3′-substituted 3′-amino-3′-deoxyadenosine analogues were synthesized and subsequently tested against the human malaria parasite Plasmodium falciparum in vitro. Several amongst them displayed pronounced antiplasmodial activities.     

Gametocytocidal activity of pyronaridine and DNA topoisomerase II inhibitors against multidrug-resistant Plasmodium falciparum in vitro

Gametocytocidal activities of pyronaridine and DNA topoisomerase II inhibitors against two isolates of multidrug-resistant Plasmodium falciparum, KT1 and KT3 were determined. After sorbitol treatment, pure gametocyte cultures of Plasmodium falciparum containing mostly young gametocytes (stage II and III) obtained on day 11 were exposed to the drugs for 48 h. The effect of the drugs on gametocyte development was assessed by counting gametocytes on day 15 of culture. Pyronaridine was the most effective gametocytocidal drug against P. falciparum isolates KT1 and KT3 with 50% inhibitory concentration of 6 and 20 nM, respectively. Moreover, the 50% inhibitory concentration of pyronaridine was lower than that of primaquine which is the only drug used to treat malaria patients harboring gametocytes. Prokaryotic (norfloxacin) and eukaryotic (amsacrine and etoposide) DNA topoisomerase II inhibitors were only effective against asexual but not sexual stages of the malaria parasites. Pyronaridine has both schizontocidal and gametocytocidal activities against the human malaria parasite, P. falciparum.     

Bicyclo[2.2.2]octyl esters of dialkylamino acids as antiprotozoals

A couple of bicyclo[2.2.2]octyl esters of 2-dialkylaminoacetic acids were prepared. Their antiplasmodial and antitrypanosomal activities against Trypanosoma brucei rhodesiense (STIB 900) and the K(1) strain of Plasmodium falciparum (resistant to chloroquine and pyrimethamine) were determined using microplate assays. Structure-activity relationships were discussed. The antiprotozoal activities were remarkably increased by insertion of a second basic centre. The selectivity indices of the most active compounds are superior in the bicyclo-octane series.     

Synthesis and structure-activity relationships for new 6-fluoroquinoline derivatives with antiplasmodial activity

The substitution of 6-fluoroquinolines was modified in ring positions 2 and 4. The new compounds were tested in vitro for their activities against a sensitive and a multidrug resistant strain of Plasmodium falciparum. Some physicochemical parametres were calculated (log P, log D, ligand efficiency) or determined experimentally (permeability). The most promising compounds were tested for their in vivo activity against Plasmodium berghei in a mouse model. The 6-fluoro-2-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-N-[2-(pyrrolidin-1-yl)ethyl]quinoline-4-carboxamide possessed proper physicochemical properties and showed high antiplasmodial activity in vitro (IC₅₀?≤?0.0029?µM) and in vivo (99.6% activity).     

Antimalarial activity enhancement in hydroxymethylcarbonyl (HMC) isostere-based dipeptidomimetics targeting malarial aspartic protease plasmepsin

Plasmepsin (Plm) is a potential target for new antimalarial drugs, but most reported Plm inhibitors have relatively low antimalarial activities. We synthesized a series of dipeptide-type HIV protease inhibitors, which contain an allophenylnorstatine-dimethylthioproline scaffold to exhibit potent inhibitory activities against Plm II. Their activities against Plasmodium falciparum in the infected erythrocyte assay were largely different from those against the target enzyme. To improve the antimalarial activity of peptidomimetic Plm inhibitors, we attached substituents on a structure of the highly potent Plm inhibitor KNI-10006. Among the derivatives, we identified alkylamino compounds such as 44 (KNI-10283) and 47 (KNI-10538) with more than 15-fold enhanced antimalarial activity, to the sub-micromolar level, maintaining their potent Plm II inhibitory activity and low cytotoxicity. These results suggest that auxiliary substituents on a specific basic group contribute to deliver the inhibitors to the target Plm.