Thieno[2,3-c]quinolines - synthesis and biological investigation

pH-Dependant reduction of the methyl 3-(2-nitrophenyl)thiophene-2-carboxylate (3), obtained by Suzuki cross-coupling of the methyl 3-iodothiophene-2-carboxylate with 2-nitrophenyl boronic acid yields the cyclic hydroxamic acid 4 and the lactam 5, respectively. The lactam 5 is also formed by reacting the compound 2 with pinacolato 2-aminophenylboronate. The 4-chlorothieno[2,3-c]quinoline 6 is formed from the lactam 5 by heating with POCl3/PCl5. Melting of 6 with the novaldiamine base in phenol gives the chloroquine analogue 7, whereas the amodiaquine and the cycloquine analogues 8 and 9 are obtained using phenol Mannich bases. The hydroxamic acid 4 has a moderate effect on eicosanoid biosynthesis in human whole blood. The growth of the chloroquine resistent Plasmodium falciparum strain Dd2 is inhibited by the pyronaridine derivative 9 with an IC50 value of 650 nM.     

1]Benzofuro[3,2-b]pyridin-4-yl-amines - synthesis and investigation of activity against malaria

The ethyl 4-chlorobenzofuro[3,2-b]pyridine-3-carboxylate (2) reacted with the hydrochlorides of the mono- and bis-phenol Mannich bases 3 to yield the amodiaquine and pyronaridine analogues 4. The chloroquine analogue 6 was formed by melting 2 with the novaldiamine base (5) in phenol. The most active compound 4c inhibited the growth of the malaria parasite Plasmodium falciparum with an IC50 of 500 nM.     

1]Benzothieno[3,2-b]pyridin-4-yl-amine--synthesis and investigation of activity against malaria

The ethyl 4-chlorobenzothieno[3,2-b]pyridine-3-carboxylate (2) reacted with the hydrochlorides of the mono- and bis-phenol Mannich bases 6 to yield the amodiaquine and pyronaridine analogues 9. The chloroquine analogue 10 was formed by melting 2 with the novaldiamine base (7) in phenol. The stability of the 4-aminophenols 9 was investigated by anodic oxidation using the rotating platinum electrode by means of difference pulse voltammetry. The half wave potentials were measured giving E(1/2) approximately 1.05 V. Compound 9g displayed the highest activity against the growth of the malaria parasite Plasmodium falciparum. Testing against the chloroquine sensitive 3D7 and the chloroquine resistant Dd2 strain resulted in IC50 values of 150 nM and 210 nM, respectively. Surprisingly, the 3-carbinol 4 and the 3-chloromethyl derivative 5, synthesized from the 3-carboxylic acid ester 2, reacted with the phenol Mannich base 6a and the novaldiamine base (7), respectively, to yield the 4-pyridone 8.     

Thieno[3,4-c]quinoline-4-yl-amines--synthesis and investigation of activity against malaria

The 4-aryl derivative 3, obtained by Suzuki cross coupling of the methyl 4-bromothiophene-3-carboxylate (2) with 2-nitrophenylboronic acid cyclizes under reductive conditions pH-dependant to yield the tricyclic hydroxamic acid 4 or the lactam 5. The chlorothieno[3,4-c]quinoline 6 was formed by reaction of the lactam 5 with P,P-dichlorophenylphosphinoxide. The amines 7-14 were synthesized from the chloroimine 6. Compounds 7a,b, 8, 9, 10b, 11, 12 and 14a, b were tested for in vitro antimalarial activity using the chloroquine sensitive 3D7 and the chloroquine resistant Plasmodium falciparum strain Dd2. The highest activity were shown by 10b with IC50 values of 130 nM and 50 nM, respectively and by 11 with IC50 values of 190 nM and 44 nM, respectively.     

Pyrido [3,2-b]indol-4-yl-amines--synthesis and investigation of activity against malaria

Pyrido[3,2-b]indol-4-yl-amines--synthesis and investigation of activity against malaria Starting with 3-aminoindole-2-carboxylic acid ester 1 the annulated pyrido[3,2-b]indoles 6 and 8 were synthesized as key substances. The 4-chloropyridine derivative 8 reacted with the phenol Mannich bases 11 and the novaldiamine base 13, respectively, to yield the amodiaquine and cycloquine analogues 12 as well as the chloroquine analogue 14. The stability of the compounds 12 and 14 were proven by the half wave potentials measured by differential pulse voltammetry. Compounds 12 and 14 were tested for in vitro antimalarial activity using a chloroquine sensitive and a chloroquine resistant Plasmodium falciparum strain. The highest activity was shown by 12g with IC50 values of 50 nM and 38 nM, respectively. The in vivo activity of 12g was tested in Plasmodium vinckei infected mice resulting in ED50 values of 22 mg/kg and 26 mg/kg after intraperitoneal and oral administration, respectively.     

Pyrrolo[3,2-c]quinoline derivatives: a new class of kynurenine-3-hydroxylase inhibitors.

A series of pyrrolo[3,2-c]quinoline derivatives were synthesised and evaluated as inhibitors of selected enzymes of the kynurenine pathway. 7-Chloro-3-methyl-1H-pyrrolo[3,2-c]quinoline-4-carboxylic acid (7a) was found to be a relatively potent and selective inhibitor of kynurenine-3-hydroxylase (KYN-3-OHase). A molecular modelling study showed a good superimposition of 7a with PNU-156561 and kynurenine the natural substrate of KYN-3-OHase.     

普卢利沙星的合成

用3,4-二氟苯胺制得6,7-二氟-4-羟基-2-甲氧甲硫基喹啉-3-羧酸乙酯,在乙醇中与盐酸反应得到巯基化合物后,经与1,1-二碘乙烷环合、与哌嗪缩合、酸性水解得到6-氟-1-甲基-4-氧代-7-(1-哌嗪基)-1H,4H-[1,3]硫氮杂环丁烷并[3,2-a]喹啉-3-羧酸,最后与由3-羟基-2-丁酮和三光气反应后溴代得到的4-溴甲基-5-甲基-1,3-二噁环戊烯-2-酮缩合,得到氟喹诺酮类抗菌药普卢利沙星,总收率26%(以3,4-二氟苯胺计).     

Inhibition of efflux of quinolines as new therapeutic strategy in malaria

Plasmodium falciparum is one of the most lethal parasite responsible for human malaria. Until now, the only one solution to counter malaria is the use of antimalarial drugs. Unfortunately, the extensively use of drugs, such as quinolines (i.e. chloroquine, quinine or mefloquine), have led to the emergence of drug resistance. Chloroquine and probably other quinolines act in interfering in the detoxification of hematin in the digestive vacuole. Quinolines are accumulated in P. falciparum digestive vacuole and the accumulation varies from a susceptible strain to a resistant one. Nevertheless, the mechanisms of quinoline resistance are still investigating. Genetic polymorphisms in some strains have been linked to drug resistance. The modifications observed are mutations on genes that encode transport proteins localized in the membrane of digestive vacuole. Three transporters were involved in quinoline resistance: PfCRT (Plasmodium falciparum chloroquine resistance transporter), Pgh1 (P-glycoprotein homologue 1) and PfMRP (Plasmodium falciparum multidrug resistance protein). They could be involved in accumulation or efflux mechanisms of drugs. In order to understand their role in resistance, localization, encoding gene structure, protein structure and endogenous function of these three transporters are reported. Some molecules that have no intrinsic antimalarial effect have been shown to reverse drug resistance when they are combined to chloroquine, quinine or mefloquine. These molecules are a solution to counter resistance but also they are precious tools to elucidate the resistance mechanisms. The molecules that have already shown a capacity to reverse chloroquine, quinine or mefloquine resistances were reported. Some of them could act on one of the three transporters involved in drug resistance, by confirming their role in quinoline resistance. Here we summarize the main elements of quinoline resistance and reversion of quinoline resistance related to malaria.     

Synthesis and in vitro and in vivo antimalarial activity of N1-(7-chloro-4-quinolyl)-1,4-bis(3-aminopropyl)piperazine derivatives

Three series of monoquinolines consisting of a 1,4-bis(3-aminopropyl)piperazine linker and a large variety of terminal groups were synthesized. Our aim was to prove that in related bisquinoline, it is the second quinoline moiety that is responsible for cytotoxicity and that it is not an absolute requirement for overcoming resistance to chloroquine (CQ). Eleven compounds displayed a higher selectivity index (ratio CC50/IC50 activity) than CQ, and one of them cured mice infected by Plasmodium berghei.     

Synthesis of novel quinolines, pyranoquinolines, furoquinolines, thieno-quinoline and their effect on the ultrastructure of some pathogenic microorganisms.

New series of quinolines 2, 6, 7, 9, 14-17, 20, 21; pyrano[3,2-c]quinolines 3, 4, 5, 11; furo[3,2-c]quinolines 8, 18; oxazino[5,6-c]quinoline 19 and thieno[3,4-b]quinoline 22 were prepared and the impact of synthesized compounds on some pathogenic microorganisms isolated from clinical samples was studied. Compounds 4, 11 and 14 were found to be the most active against all tested microorganisms. The compound 14 which showed higher activity was selected to study its action on the ultrastructure of Pseudomonas aeruginosa, Staphylococcus aureus and Candida albicans. Death of numerous cells, destruction of the cell wall, cell contents poured into the medium and impairment of metabolism, were observed.     

Inhibitory effect on the release of mediators from rat peritoneal exudate cells and the antagonistic effect against mediators of MY-5116 and other anti-allergic agents

The effects of a new anti-allergic agent, MY-5116: isoamyl 5,6-dihydro-7,8-dimethyl-4,5-dioxo-4H-pyrano [3,2-c] quinoline-2-carboxylate, and its main metabolite, MY-1250: 5,6-dihydro-7,8-dimethyl-4,5-dioxo-4H-pyrano [3,2-c] quinoline-2-carboxylic acid, on 48 hr homologous PCA (PCA) in rats and the release of histamine and SRS from rat peritoneal exudate cells (PEC) induced by IgE antibody in comparison with other anti-allergic agents were investigated. Also, the effects of MY-5116 and MY-1250 on antagonistic action against histamine and LTD4 were studied. MY-5116, tranilast and ketotifen inhibited PCA at oral doses of more than 3 mg/kg, 300 mg/kg and 0.3 mg/kg, respectively. MY-1250, DSCG and tranilast inhibited significantly the release of histamine from PEC induced by the antigen-antibody reaction in a dose-dependent manner, and the values of IC50 were 4.9 X 10(-8), 4.8 X 10(-6) and 4.6 X 10(-6) g/ml, respectively. Ketotifen inhibited significantly the release of histamine at a concentration of 10(-5) g/ml, but it accelerated significantly the release of histamine from PEC at a concentration of 10(-4) g/ml. MY-1250 and tranilast suppressed the release of SRS from PEC induced by the antigen-antibody reaction. The values of IC50 of MY-1250 and tranilast were 1.5 X 10(-6) and 2.1 X 10(-6) g/ml, respectively. MY-1250 suppressed slightly the release of SRS from PEC induced by A23187. MY-5116 showed no effect on the increase of vascular permeability induced by histamine, bradykinin and serotonin in rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

抗疟药双咯喹及其类似物的合成

报道了双咯喹(4)和同类抗疟药阿莫地喹(1)、环喹(2)、阿莫吡喹(3)及衍生物5～14的合成,均用烷基胺与4-(4-羟基苯胺基)-7-氯喹啉进行Mannich反应而得。对鼠伯氏疟原虫的作用,以4及3最强;毒性均低于氯喹;与氯喹的交叉抗性指数分别为4及5。4治疗间日疟病人的疗效与氯喹相当。1,2,3,7,8还具有抗小鼠日本血吸虫的作用。     

Prevention and treatment of malaria: in vitro evaluation of new compounds]

One of the current options for reducing the morbidity and mortality of malaria are chemoprophylaxis and chemotherapy. For this reason, the increasing prevalence of strains of Plasmodium falciparum resistant to chloroquine and other antimalarial drugs poses a serious problem for control of malaria. There is an urgent need to find and develop novel compounds and to identify novel chemotherapeutic targets. Different approaches to discover new compounds are presented from examples of molecules studied in the Tropical Medicine Institute of the French Army Health Service (IMTSSA) evaluation against isolates of compounds in pharmaceutical development in collaboration with pharmaceuticals (pyronaridine, benflumetol, ferrochloroquine), screening of molecules which are still registered for other pathologies (antibiotics), screening of new synthesized compounds (artemisinin derivatives) and identification of parasitical targets and essential metabolic ways for parasite, and identification of molecules acting on these targets (reversal of resistance to chloroquine, iron chelators).     

4‐Aminoquinoline‐β‐Lactam Conjugates: Synthesis,Antimalarial, and Antitubercular Evaluation

A library of quinoline‐β‐lactam‐based hybrids was synthesized and tested for their antimalarial and antitubercular activities. The present antimalarial data showed the dependence of activity on the nature of linker, N‐1 substituent of the β‐lactam ring as well as the length of alkyl chain. Most of the compounds are not as efficient as chloroquine in inhibiting the culture growth of Plasmodium falciparum W2 strain. Nevertheless, the synthesized hybrids showed better antitubercular activities (up to five times) compared with cephalexin (up to three times) and ethionamide.     

MY-1250, a major metabolite of the anti-allergic drug repirinast, induces phosphorylation of a 78-kDa protein in rat mast cells.

Repirinast (MY-5116; isoamyl 5,6-dihydro-7,8-dimethyl-4,5-dioxo-4H-pyrano [3,2-c]quinoline-2-carboxylate) is an anti-allergic drug of demonstrated effectiveness for treating bronchial asthma in humans. MY-1250 (5,6-dihydro-7,8-dimethyl-4,5-dioxo-4H-pyrano [3,2-c]quinoline-2-carboxylic acid), the major active metabolite of repirinast, inhibits antigen-induced histamine release from sensitized rat peritoneal exudate cells (PEC). When purified rat mast cells were treated with MY-1250 (2.5 x 10(-5) M) for 1 min, phosphorylation of a specific mast cell protein of apparent molecular mass of 78 kDa was observed as previously reported for sodium cromoglycate (SCG). Phosphorylation of this protein induced by MY-1250 and SCG occurred in a concentration-dependent manner with IC50 values of 2.0 x 10(-7) and 1.4 x 10(-5) M, respectively. MY-1250 did not inhibit calcium ionophore A23187 (1 microgram/mL)-induced histamine release from rat PEC. In the presence of calcium ionophore A23187 (1 microgram/mL), phosphorylation of this protein induced by MY-1250 was not evident. In conclusion, MY-1250 induced phosphorylation of a 78-kDa protein in rat mast cells and MY-1250 may inhibit histamine release by regulating phosphorylation of this protein in rat mast cells.     

Chemical and pharmacological research on pyran derivatives. XIII. Derivatives of 2H-pyrano/3,2-c/quinoline]

Treatment of N-alkylanilines or diphenylamine with N,N-dialkylethoxycarbonylacetamides in the presence of phosphorus oxychloride afforded 6-alkyl(phenyl)-4-dialkylaminopyrano [3,2-c] quinoline-2,5-(6H)-diones, two molecules of amide being involved in the reaction. In some instances 6-alkyl(phenyl)-4-alkylaminopyrano [3,2-c] quinoline-2,5(6H)-diones were obtained through a partial dealkylation of the amino group. Pharmacological evaluation of some compounds showed no activity on the CNS.     

Reversal activity of the naturally occurring chemosensitizer malagashanine in Plasmodium malaria

Malagashanine (MG) is the parent compound of a new type of indole alkaloids, the N(b)C(21)-secocuran, isolated so far from the Malagasy Strychnos species traditionally used as chloroquine adjuvants in the treatment of chronic malaria. Previously, it was shown to have weak in vitro intrinsic antiplasmodial activity (IC(50) = 146.5 +/- 0.2 microM), but did display marked in vitro chloroquine-potentiating action against the FcM29 chloroquine-resistant strain of Plasmodium falciparum. The purpose of the present study was to further investigate its reversal activity. Thus, the previous in vitro results were tested in vivo. The interaction of MG with several antimalarials against various strains of P. falciparum was also assessed. As expected, MG enhanced the effect of chloroquine against the resistant strain W2, but had no action on the susceptible strain 3D7 and two sensitive isolates. Interestingly, MG was found to exhibit significant chloroquine-potentiating action against the FcB1 strain formerly described as a resistant strain but one which has since lost its resistance for unknown reasons. One other relevant result that arose from our study was the observation of the selective enhancing action of MG on quinolines (chloroquine, quinine, and mefloquine), aminoacridines (quinacrine and pyronaridine), and a structurally unrelated drug (halofantrine), all of which are believed to exert their antimalarial effect by binding with haematin. MG was finally found to specifically act with chloroquine on the old trophozoite stage of the P. falciparum cycle. Similarities and differences between verapamil and MG reversal activity are briefly presented.     

Synthesis and antiprotozoal activity of [1,3]oxazino[4,5,6-de]quinolines

The synthesis of 1,3-oxazino-anellated 4-amino-5-hydroxy-quinolines has been investigated. Cyclisation to 2,3-dihydro[1,3]oxazino[4,5,6-de]quinoline-2-ones/-2-thiones (2/3) was achieved by reaction with 1,1'-carbonyldiimidazole or 1,1'-thiocarbonyldiimidazole. Cyclocondensation with aldehydes yielded 2,3-dihydro[1,3]oxazino[4,5,6-de]quinoline-derivatives (5). All new tricyclic compounds exhibited weak antiprotozoal activity against Plasmodium falciparum.     

Reduced levels of chloroquine resistant Plasmodium falciparum in selected foci of the South West Province,Cameroon

OBJECTIVES: To evaluate the state of chloroquine resistant malaria in the South West Province of Cameroon. To estimate the prevalence of different species of Plasmodium in the area. DESIGN: A cross sectional study. SETTING: South West Province of Cameroon. SUBJECTS: 326 febrile patients. MAIN OUTCOME MEASURES: Chloroquine resistance studies using the WHO seven-day standard in vivo test. Speciation of malaria by polymerase chain reaction. Prevalence of falciparum malaria by light microscopy of thick blood smears. RESULTS: Prevalence of chloroquine resistance ranged from 4.3 to 13.2%. A total of six cases showed RIII resistance, and three cases showed RII resistance. Plasmodium falciparum was the predominant species, 96.8% of those testing positive for P. falciparum, 6.3% of cases showed mixed infections of P. falciparum and P. malariae. P. ovale accounted for 3% of cases. CONCLUSION: P. falciparum resistance to chloroquine may not be on the increase compared to earlier reports from the South West Province. The results have important implications in treatment of malaria in view of the low cost of chloroquine.     

抗疟新药7351的合成

A new antimalarial drug 7351 (pyronaridine or malaridine), 2-methoxy-7-chloro10-[3', 5'-his- (pyrrolin-1-yl-methyl)-4'-hydroxyphenylamino]-benzo-[b]- 1,5-naphthy-ridine (Ⅱ_b), was synthesized. Experimental therapy and clinical trials showed that the results are satisfactory. No cross-resistance to chloroquine has been found in animals and in human cases. The drug could be given by oral, intramuscular injection or intravenous drip. It is specific for treatment of severe malaria cases.