Potential Antimalarials. VIII. Mono- and Di-mannich Bases of 2-(7′-Trifluoro-methylquinolin-4′-ylamino)phenol Via 2-Nitrophenols

1989 ◽  
Vol 42 (12) ◽  
pp. 2191 ◽  
Author(s):  
GB Barlin ◽  
JH Yan
Keyword(s):  
Plasmodium Falciparum ◽  
Mannich Bases ◽  
Nitro Compounds ◽  
Resistant Isolate ◽  
Sensitive Isolate

Di-Mannich bases have been prepared by the reaction of 2-nitrophenol and formaldehyde with dimethylamine, diethylamine, dipropylamine, pyrrolidine, piperidine, 2-, 3- and 4-methylpiperidine, 3,5-dimethylpiperidine and morpholine. The nitro compounds were reduced catalytically to the corresponding 2-aminophenols which with 4-chloro-7-trifluoromethylquinoline gave the di-Mannich bases of 2-(7′-trifluoromethylquinolin-4′-ylamino)phenol. Analogous compounds were synthesized from 3-and 5-methyl-2-nitrophenols, and pyrrolidine. The mono-Mannich compounds, 6-(3′-methylpiperidin-1′-ylmethyl)- and 6-(pyrrolidin-1′- ylmethyl)-2-(7″-trifluoromethylquinolin-4″-ylamino)pheno, were also prepared. The results for tests against a chloroquine-sensitive isolate (FCQ-27) and chloroquine-resistant isolate (K-1) of Plasmodium falciparum are reported.

scholarly journals Chemosensitization of Plasmodium falciparum by Probenecid In Vitro

2003 ◽  
Vol 47 (7) ◽  
pp. 2108-2112 ◽  
Author(s):  
Alexis Nzila ◽  
Eddy Mberu ◽  
Pat Bray ◽  
Gilbert Kokwaro ◽  
Peter Winstanley ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Drug Transport ◽  
Human Tumor ◽  
Resistant Isolate ◽  
Transport Mechanisms ◽  
Human Tumor Cells ◽  
Sensitive Isolate ◽  
Parasite Viability ◽  
Antifolate Resistance

ABSTRACT Resistance to drugs can result from changes in drug transport, and this resistance can sometimes be overcome by a second drug that modifies the transport mechanisms of the cell. This strategy has been exploited to partly reverse resistance to chloroquine in Plasmodium falciparum. Studies with human tumor cells have shown that probenecid can reverse resistance to the antifolate methotrexate, but the potential for reversal of antifolate resistance has not been studied in P. falciparum. In the present study we tested the ability of probenecid to reverse antifolate resistance in P. falciparum in vitro. Probenecid, at concentrations that had no effect on parasite viability alone (50 μM), was shown to increase the sensitivity of a highly resistant parasite isolate to the antifolates pyrimethamine, sulfadoxine, chlorcycloguanil, and dapsone by seven-, five-, three-, and threefold, respectively. The equivalent effects against an antifolate-sensitive isolate were activity enhancements of approximately 3-, 6-, 1.2-, and 19-fold, respectively. Probenecid decreased the level of uptake of radiolabeled folic acid, suggesting a transport-based mechanism linked to folate salvage. When probenecid was tested with chloroquine, it chemosensitized the resistant isolate to chloroquine (i.e., enhanced the activity of chloroquine). This enhancement of activity was associated with increased levels of chloroquine accumulation. In conclusion, we have shown that probenecid can chemosensitize malaria parasites to antifolate compounds via a mechanism linked to reduced folate uptake. Notably, this effect is observed in both folate-sensitive and -resistant parasites. In contrast to the activities of antifolate compounds, the effect of probenecid on chloroquine sensitivity was selective for chloroquine-resistant parasites (patent P407595GB [W. P. Thompson & Co., Liverpool, United Kingdom] has been filed to protect this intellectual property).

Potential Antimalarials. XII. 4-Chloro-3-(substituted amino)methyl-5-[7-bromo (and 7-trifluoromethyl)-1,5-naphthyridin-4-ylamino]biphenyl-2-ols and 4-Chloro-3-(substituted amino)methyl-5-(7-trifluoromethyl-quinazolin-4-ylamino)biphenyl-2-ols

1990 ◽  
Vol 43 (8) ◽  
pp. 1367 ◽  
Author(s):  
GB Barlin ◽  
C Jiravinyu
Keyword(s):  
Plasmodium Falciparum ◽  
Antimalarial Activity ◽  
Mannich Bases ◽  
Sensitive Isolate

The mono- Mannich bases 3-(t- butylamino )methyl-4?-chloro-, 3-(4- benzylpiperidin-1-yl)methyl-4′-chloro-, 3-(4-benzylpiperazin-1- yl )methyl-4′-chloro-, 4′-chloro-3-diethylaminomethyl-, 4′-chloro-3-(pyrrolidin-1-yl)methyl-, 4′-chloro-3-(piperidin-1-yl)methyl- and 4′-chloro-3-(3- and 4- methylpiperidin-1-yl)methyl-5-[7-bromo (and 7- trifluoromethyl )-1,5-naphthyridin-4-ylamino]- biphenyl-2-ol, and the corresponding substituted 5-(7-trifluoromethylquinazolin-4-ylamino)bi- phenyl-2-ols, have been prepared by condensation of the 5-amino-3-(N- substituted aminomethyl )-4′-chlorobiphenyl-2-ols and the appropriate 4-chloro heterocycle. The antimalarial activity of these products against the chloroquine-sensitive isolate (FCQ-27) of Plasmodium falciparum revealed that the 1,5-naphthyridines reported here were less active than the corresponding di-Mannich bases, e.g. (6), derived from 4-[7- bromo (and 7-trifluoromethyl)-1?,5′-naphthyridin-4′-ylamino]phenol, a feature not shared by the corresponding quinazolines.

Potential Antimalarials. XIV. Mono-Mannich Bases of 4-[7'-Bromo (and trifluoromethyl)-1',5'-naphthyridin-4'-yl-amino]-5,6,7,8-tetrahydronaphthalen-1-ols

1991 ◽  
Vol 44 (5) ◽  
pp. 677 ◽  
Author(s):  
GB Barlin ◽  
C Jiravinyu ◽  
JH Yan
Keyword(s):  
Plasmodium Falciparum ◽  
Mannich Bases ◽  
Significant Activity ◽  
Mannich Reactions ◽  
Amino Compounds ◽  
In Vivo Tests ◽  
Sensitive Isolate ◽  
Plasmodium Vinckei

The mono- Mannich bases 2-diethylaminomethyl-, 2-t-butylaminomethyl-, 2-(pyrrolidin-1-ylmethyl)-, 2-(piperidin-1-ylmethyl)-, 2-(3-and 4-methylpiperidin-1-ylmethyl)-, 2-(4-benzylpip- eridin-1-ylmethyl)- and 2-(4-benzylpiperazin-1-ylmethyl)-4-[7-bromo (and 7-trifluoromethyl)- 1,5-naphthyridin-4-ylamino]-5,6,7,8-tetrahydronaphthalen-1-ols have been prepared from 4- acetamido-5,6,7,8-tetrahydronaphthalen-1-ols by Mannich reactions followed by hydrolysis to the 4-amino compounds and condensation with the relevant 4-chloro heterocycle. The antimalarial activities of these compounds against the chloroquine -sensitive isolate (FCQ-27) of Plasmodium falciparum in vitro are reported; 4-(7-bromo-1,5-naphthyridin-4-yl)amino-2-(t- butylaminomethyl )-5,6,7,8-tetrahydronaphthalen-1-ol was about twice as active as chloroquine . In in vivo tests against Plasmodium vinckei vinckei in mice this compound exhibited significant activity. The 7-bromo compounds were more active than their 7-trifluoromethyl analogues.

scholarly journals Characterization of the Proliferating Cell Nuclear Antigen of Leishmania donovani Clinical Isolates and Its Association with Antimony Resistance

2014 ◽  
Vol 58 (6) ◽  
pp. 2997-3007 ◽  
Author(s):  
Rati Tandon ◽  
Sharat Chandra ◽  
Rajendra Kumar Baharia ◽  
Sanchita Das ◽  
Pragya Misra ◽  
...  
Keyword(s):  
Clinical Isolate ◽  
Proliferating Cell Nuclear Antigen ◽  
Leishmania Donovani ◽  
Clinical Isolates ◽  
Resistant Isolate ◽  
Nuclear Antigen ◽  
Wild Type ◽  
Content Type ◽  
Sensitive Isolate ◽  
Proliferating Cell

ABSTRACTPreviously, through a proteomic analysis, proliferating cell nuclear antigen (PCNA) was found to be overexpressed in the sodium antimony gluconate (SAG)-resistant clinical isolate compared to that in the SAG-sensitive clinical isolate ofLeishmania donovani. The present study was designed to explore the potential role of the PCNA protein in SAG resistance inL. donovani. For this purpose, the protein was cloned, overexpressed, purified, and modeled. Western blot (WB) and real-time PCR (RT-PCR) analyses confirmed that PCNA was overexpressed by ≥3-fold in the log phase, stationary phase, and peanut agglutinin isolated procyclic and metacyclic stages of the promastigote form and by ∼5-fold in the amastigote form of the SAG-resistant isolate compared to that in the SAG-sensitive isolate.L. donovaniPCNA (LdPCNA) was overexpressed as a green fluorescent protein (GFP) fusion protein in a SAG-sensitive clinical isolate ofL. donovani, and modulation of the sensitivities of the transfectants to pentavalent antimonial (SbV) and trivalent antimonial (SbIII) drugs was assessedin vitroagainst promastigotes and intracellular (J774A.1 cell line) amastigotes, respectively. Overexpression of LdPCNA in the SAG-sensitive isolate resulted in an increase in the 50% inhibitory concentrations (IC50) of SbV(from 41.2 ± 0.6 μg/ml to 66.5 ± 3.9 μg/ml) and SbIII(from 24.0 ± 0.3 μg/ml to 43.4 ± 1.8 μg/ml). Moreover, PCNA-overexpressing promastigote transfectants exhibited less DNA fragmentation compared to that of wild-type SAG-sensitive parasites upon SbIIItreatment. In addition, SAG-induced nitric oxide (NO) production was found to be significantly inhibited in the macrophages infected with the transfectants compared with that in wild-type SAG-sensitive parasites. Consequently, we infer that LdPCNA has a significant role in SAG resistance inL. donovaniclinical isolates, which warrants detailed investigations regarding its mechanism.

Potential Antimalarials. XVI. 4'-Chloro-3-[7″-chloro(and trifluoromethyl)quinolin-4″-yl]amino-5-(substituted amino)methylbiphenyl-4-ols and 4'-Bromo(and 3'-trifluoromethyl)-3-(substituted amino)methyl-5-(7″-trifluoromethylquinolin-4″-yl)aminobiphenyl-2-ols

1992 ◽  
Vol 45 (11) ◽  
pp. 1845 ◽  
Author(s):  
GB Barlin ◽  
FL Tian ◽  
B Kotecka ◽  
KH Rieckmann
Keyword(s):  
Plasmodium Falciparum ◽  
Antimalarial Activity ◽  
Mannich Bases ◽  
In Vitro Tests ◽  
Ic50 Values

Twenty-four mono-Mannich bases of the general formulae 4'-chloro-3-[7″-chloro(and trifluoro-methyl)quinolin-4'-yl]amino-5-(substituted amino)methylbiphenyl-4-ols and 4'-bromo(and 3'- trifluoromethyl-3(substituted amino)methyl-5(7″-trifluoromethylquinolin-4″-yl) aminobiphenyl-2-ols have been prepared by condensation of the 4-chloro heterocycle with 5-amino-3-(N-substituted amino)methyl-4'-chlorobiphenyl-4-ols or 5-amino-3-(N-substituted amino)methyl- 4'-bromo(or 3'-trifluoromethyl)biphenyl-2-ols. The antimalarial activity of these products in in vitro tests against Plasmodium falciparum reveals many with IC50 values of 50-100 nM ( chloroquine 20-40 nM ). The biphenyl-2-ols were more active than comparable biphenyl-4-ols.

scholarly journals Triazole Sensitivity in a Contemporary Population of Fusarium graminearum from New York Wheat and Competitiveness of a Tebuconazole-Resistant Isolate

Plant Disease ◽  
2014 ◽  
Vol 98 (5) ◽  
pp. 607-613 ◽  
Author(s):  
Pierri Spolti ◽  
Emerson M. Del Ponte ◽  
Yanhong Dong ◽  
Jaime A. Cummings ◽  
Gary C. Bergstrom
Keyword(s):  
New York ◽  
Fusarium Graminearum ◽  
Mycelial Growth ◽  
Field Isolate ◽  
Effective Concentration ◽  
Resistant Isolate ◽  
Head Blight ◽  
Future Studies ◽  
Sensitive Isolate ◽  
Mean Sensitivity

A sample of 50 isolates, including 25 each of the 3-acetyldeoxynivalenol and the 15-acetyldeoxynivalenol trichothecene genotype, from a contemporary collection of Fusarium graminearum associated with Fusarium head blight (FHB) of wheat in New York varied in sensitivity to tebuconazole (effective concentration leading to a 50% reduction of mycelial growth [EC50] of 0.28 to 8.09 mg/liter; μ = 1.12 mg/liter) and metconazole (0.05 to 0.86 mg/liter; μ = 0.33). Mean sensitivity did not differ between the trichothecene genotype groups. Isolate Gz448NY11 from Steuben County is the first tebuconazole-resistant field isolate of F. graminearum reported in the Americas and has the lowest sensitivity to tebuconazole (EC50 = 8.09 mg/liter) documented for this species. Suppression of FHB and deoxynivalenol (DON) following application of a commercial rate of tebuconazole was significantly diminished in plants inoculated with the tebuconazole-resistant isolate compared with those inoculated with a tebuconazole-sensitive isolate well documented for its aggressiveness and toxigenicity on wheat. There was no diminution of FHB and DON suppression with either isolate following application of metconazole. Significantly more individuals of the tebuconazole-resistant isolate were recovered from spikes inoculated with an equal mixture of the two isolates and sprayed with tebuconazole. Future studies are needed on the epidemiology and monitoring of triazole-resistant isolates to understand the risk that fungicide resistance poses to disease management and food security.

Potential Antimalarials. IX. Di-mannich Bases of 4-(7′-trifluoro-methylquinazolin-4′-ylamino)phenol and 4-(7′-Trifluoromethylquinolin-4′-ylamino)phenol

1990 ◽  
Vol 43 (2) ◽  
pp. 311 ◽  
Author(s):  
GB Barlin ◽  
C Jiravinyu
Keyword(s):  
Plasmodium Falciparum ◽  
Antimalarial Activity ◽  
Mannich Bases

Syntheses are reported for a series of di-Mannich bases of 4-(7′-trifluoromethylquinazolin-4′-ylamino)phenol derived from 4-chloro-7-trifluoromethylquinazoline with the di-Mannich bases of 4-aminophenol. Some analogous quinolines were prepared similarly. When tested for antimalarial activity against Plasmodium falciparum in vitro, the quinazolines were rather less active than the corresponding quinolines.

scholarly journals Resistance to Fluopicolide and Propamocarb and Baseline Sensitivity to Ethaboxam Among Isolates of Pseudoperonospora cubensis From the Eastern United States

Plant Disease ◽  
2018 ◽  
Vol 102 (8) ◽  
pp. 1619-1626 ◽  
Author(s):  
A. Thomas ◽  
K. N. Neufeld ◽  
K. W. Seebold ◽  
C. A. Braun ◽  
M. R. Schwarz ◽  
...  
Keyword(s):  
United States ◽  
New York ◽  
Leaf Disc ◽  
The United States ◽  
Resistant Isolate ◽  
Pseudoperonospora Cubensis ◽  
Eastern United States ◽  
Baseline Sensitivity ◽  
Highly Sensitive ◽  
Sensitive Isolate

Chemical control is currently the most effective method for controlling cucurbit downy mildew (CDM) caused by Pseudoperonospora cubensis. Most commercial cucurbit cultivars, with the exception of a few new cucumber cultivars, lack adequate disease resistance. Fluopicolide and propamocarb were among the most effective fungicides against CDM in the United States between 2006 and 2009. Since then, reduced efficacy of these two fungicides under field conditions was reported starting around 2013 but occurrence of resistance to fluopicolide and propamocarb in field isolates of P. cubensis had not been established. Thirty-one isolates collected from cucurbits in the eastern United States were tested for their sensitivity to fluopicolide and propamocarb using a leaf disc assay. This same set of isolates and four additional isolates (i.e., 35 isolates) were also used to establish the baseline sensitivity of P. cubensis to ethaboxam, an ethylamino-thiazole-carboxamide fungicide, which was recently granted registration to control CDM in the United States. About 65% of the isolates tested were resistant to fluopicolide with at least one resistant isolate being present in samples collected from 12 of the 13 states in the eastern United States. About 74% of the isolates tested were sensitive to propamocarb with at least one resistant isolate being among samples collected from 8 of the 12 states in the study. The frequency of resistance to fluopicolide and propamocarb was high among isolates collected from cucumber, while the frequency was low among isolates collected from other cucurbit host types. All isolates tested were found to be sensitive to ethaboxam and EC50 values ranged from 0.18 to 3.08 mg a.i./liter with a median of 1.55 mg a.i./liter. The ratio of EC50 values for the least sensitive and the most sensitive isolate was 17.1, indicating that P. cubensis isolates were highly sensitive to ethaboxam. The most sensitive isolates to ethaboxam were collected from New York, North Carolina, and Ohio, while the least sensitive isolates were collected from Georgia, Michigan, and New Jersey. These results show that ethaboxam could be a viable addition to fungicide programs used to control CDM in the United States.

scholarly journals Relationship between Antimalarial Drug Activity, Accumulation, and Inhibition of Heme Polymerization in Plasmodium falciparum In Vitro

1998 ◽  
Vol 42 (3) ◽  
pp. 682-686 ◽  
Author(s):  
Shaun R. Hawley ◽  
Patrick G. Bray ◽  
Mathirut Mungthin ◽  
Jill D. Atkinson ◽  
Paul M. O’Neill ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Rational Design ◽  
Drug Action ◽  
Drug Accumulation ◽  
Vitro Activity ◽  
Resistant Isolate ◽  
In Vitro Activity ◽  
Susceptible Isolate ◽  
Level Of Agreement

ABSTRACT We have investigated the contribution of drug accumulation and inhibition of heme polymerization to the in vitro activities of a series of antimalarial drugs. Only those compounds exhibiting structural relatedness to the quinolines inhibited heme polymerization. We could find no direct correlation between in vitro activity against chloroquine-susceptible or chloroquine-resistant isolates and either inhibition of heme polymerization or cellular drug accumulation for the drugs studied. However, in vitro activity against a chloroquine-susceptible isolate but not a chloroquine-resistant isolate showed a significant correlation with inhibition of heme polymerization when the activity was normalized for the extent of drug accumulation. The importance of these observations to the rational design of new quinoline-type drugs and the level of agreement of these conclusions with current views on quinoline drug action and resistance are discussed.

Potential Antimalarials. XVII. Di- and Mono-Mannich Bases of 2(and 4)-[2(and 8)-Trifluoromethylquinolin-4-ylamino]phenol

1993 ◽  
Vol 46 (1) ◽  
pp. 21 ◽  
Author(s):  
GB Barlin ◽  
TMT Nguyen ◽  
B Kotecka ◽  
KH Rieckmann
Keyword(s):  
Plasmodium Falciparum ◽  
Mannich Base ◽  
Antimalarial Activity ◽  
Mannich Bases ◽  
Sensitive Strain ◽  
In Vitro Tests ◽  
Derivatives Of

Di- and mono-Mannich base derivatives of 2(and 4)-[2(and 8)-trifluoromethylquinolin-4-ylamino]phenols have been prepared for comparison with the 7-trifluoromethyl isomers in tests for antimalarial activity. The order of activity in in vitro tests against the FC-27 ( chloroquine -sensitive) strain of Plasmodium falciparum was 7-CF3 >> 8-CF3 > 2-CF3.

Sign in / Sign up

Export Citation Format

Share Document