Design, synthesis, molecular modeling and neuroprotective effects of a new framework of cholinesterase inhibitors for Alzheimer's disease.

In search of a novel class of compounds against Alzheimer's disease (AD), a new series of 7-chloro-aminoquinoline derivatives containing methylene spacers of different sizes between the 7-chloro-4-aminoquinoline nucleus and imino methyl substituted phenolic rings, and also their reduced analogues, were designed, synthesized and evaluated as neuroprotective agents for AD in vitro. In spite of the multifaceted feature of AD, cholinesterases continue to be powerful and substantial targets, as their inhibition increases both the level and duration of the acetylcholine neurotransmitter action. The compounds presented inhibitory activity in the micromolar range against acetylcholinesterase (AChE) (imines and amines) and butyrylcholineterase (BChE) (amines). The SAR study revealed that elongation of the imine side chain improved AChE activity, whereas the reduction of these compounds to amines was crucial for higher activity and indispensable for BChE inhibition. The most promising selective inhibitors were not cytotoxic and did not stimulate pro-inflammatory activity in glial cells. Kinetic and molecular modeling studies indicated that they also show mixed-type inhibition for both enzymes, behaving as dual-site inhibitors, which can interact with both the peripheral anionic site and the catalytic anionic site of AChE. They could therefore restore cholinergic transmission and also may inhibit the aggregation of Aß promoted by AChE. Additionally, one compound showed promising anti-inflammatory activity by reducing the microglial release of NO• at a concentration that is equivalent to the IC50 against BChE (30.32 ± 0.18 µM) and 15-fold greater than the IC50 against AChE (1.97 ± 0.20 µM).Communicated by Ramaswamy H. Sarma.

Synthesis, ß-hematin inhibition studies and antimalarial evaluation of new dehydroxy isoquine derivatives against Plasmodium berghei: A promising antimalarial agent.

Many people are affected by Malaria around the world, and the parasite is developing resistance against available drugs. Currently, isoquine and N-tert-butyl isoquine are some of the most promising antimalarial candidates that have already reached Phase I and II clinical trials, respectively. Nevertheless, pharmacodynamic studies have demonstrated that isoquine is highly sensitive to form O-glucuronide metabolite, which may affect its accumulation in tissues. To avoid the O-glucuronide formation and its negative influence in the accumulation process, a series of novel five dehydroxy isoquine derivatives were designed and prepared herein as potential antimalarial agents. By a simple three-step procedure, five dehydroxy isoquines were prepared and subsequently examined on the inhibition of haemozoin formation, the main target of the 4-aminoquinolines. Four derivatives displayed significant inhibitory activities at low IC50 values from 1.66 to 1.86 µM comparable to CQ. On the basis of the results, these four compounds were subsequently tested against Plasmodium berghei ANKA model in mice, showing to be as active as CQ with significant curative responses and parasitemia suppression in mice infected. On the other hand, these four compounds showed an acceptable non specific cytotoxicity on murine peritoneal macrophague and human erythrocyte cells. Thus, the presented data indicate that the dehydroxy isoquines 4b, 4c and 4e constitute promising cost-effective leads for the development of new antiplasmodial targeted at blood-stage malaria parasites.

Anti-Mycobacterial Evaluation of 7-Chloro-4-Aminoquinolines and Hologram Quantitative Structure-Activity Relationship (HQSAR) Modeling of Amino-Imino Tautomers.

In an ongoing research program for the development of new anti-tuberculosis drugs, we synthesized three series (A, B, and C) of 7-chloro-4-aminoquinolines, which were evaluated in vitro against Mycobacterium tuberculosis (MTB). Now, we report the anti-MTB and cytotoxicity evaluations of a new series, D (D01-D21). Considering the active compounds of series A (A01-A13), B (B01-B13), C (C01-C07), and D (D01-D09), we compose a data set of 42 compounds and carried out hologram quantitative structure-activity relationship (HQSAR) analysis. The amino-imino tautomerism of the 4-aminoquinoline moiety was considered using both amino (I) and imino (II) forms as independent datasets. The best HQSAR model from each dataset was internally validated and both models showed significant statistical indexes. Tautomer I model: leave-one-out (LOO) cross-validated correlation coefficient (q²) = 0.80, squared correlation coefficient (r²) = 0.97, standard error (SE) = 0.12, cross-validated standard error (SEcv) = 0.32. Tautomer II model: q² = 0.77, r² = 0.98, SE = 0.10, SEcv = 0.35. Both models were externally validated by predicting the activity values of the corresponding test set, and the tautomer II model, which showed the best external prediction performance, was used to predict the biological activity responses of the compounds that were not evaluated in the anti-MTB trials due to poor solubility, pointing out D21 for further solubility studies to attempt to determine its actual biological activity.

Aminoquinoline compounds: Effect of 7-chloro-4-quinolinylhydrazone derivatives against Leishmania amazonensis.

In this study, we have investigated the antileishmanial activity of ten 7-chloro-4-quinolinylhydrazone derivatives. Among the compounds tested, compounds 2a and 2j presented activity against promastigotes (IC50 values of 52.5 and 21.1 µM, respectively) and compounds 2a and 2c were active against intracellular amastigotes (IC50 of 8.1 and 15.6 µM, respectively) of Leishmania amazonensis. The majority of compounds did not show toxicity against murine macrophages. Compound 2a exhibited low cytotoxicity to human erythrocytes and induced an oxidative imbalance in promastigote forms, reflected by an increase in the formation of reactive oxygen species (ROS) and a reduction of mitochondrial membrane potential. No alteration in the plasma membrane integrity of parasites was observed. Taken together, these results suggest that compound 2a is a selective antileishmanial agent, and preliminary observations suggest that its effects appear to be mediated by mitochondrial dysfunction.

1-(7-chloro-1,4-dihydroquinolin-4-ylidene)thiosemicarbazide and its hydrochloride: evidence for the existence of a stable imine tautomer in the solid state of 4-aminoquinoline free bases, an anomalous case in nitrogen heterocycles.

In the solid state, crystals of both 1-(7-chloro-1,4-dihydroquinolin-4-ylidene)thiosemicarbazide-methanol-water (2/1/1), 2C10H9ClN4S·CH3OH·H2O, (I), and its hydrochloride salt {systematic name: [(7-chloro-1,4-dihydroquinolin-4-ylidene)azaniumyl]thiourea chloride}, C10H10ClN4S(+)·Cl(-), (II), assume the imine tautomeric form, contrary to other 4-amino-7-chloroquinolines. Of particular interest are the N-C bond lengths, which have appreciable double-bond character, and the C-N-C aromatic ring bond angle. Both of these parameters have been studied extensively in 4-amino-substituted quinolines. The crystal structures of (I) and (II) in this study provide interesting examples of the amino-imino tautomerism which exists in this class of compound and is, to the best of our knowledge, hitherto unreported.

Synthesis, ß-hematin inhibition studies and antimalarial evaluation of dehydroxy isotebuquine derivatives against Plasmodium berghei.

Diverse dehydroxy-isotebuquine derivatives were prepared by using a five step synthetic sequence in good yields. All these new 4-aminoquinolines were evaluated as inhibitors of haemozoin formation, where most of them showed a significant inhibition value (% IHF >97). The best inhibitors were tested in vivo as potential antimalarials in mice infected with Plasmodium berghei ANKA chloroquine susceptible strain, three of them (11b, 11d and 11h) displayed an antimalarial activity comparable to that of chloroquine.