Marcelle de Lima Ferreira Bispo

Anti‐Tuberculosis Evaluation and Conformational Study of N‐Acylhydrazones Containing the Thiophene Nucleus

A series of N‐acylhydrazonyl‐thienyl derivatives (compounds 2 and 3), mainly of the type 2‐(aryl‐CHNNHCOCH2)‐thiene (2: aryl = substituted‐phenyl; 3: aryl = heteroaryl) were evaluated against Mycobacterium tuberculosis. Particularly active compound was 3 (heteroaryl = 5‐nitrothien‐2‐yl or 5‐nitrofuran‐2‐yl) with MIC values of 8.5 and 9.0 μM, respectively. Moderately active compounds were compound 3 (heteroaryl = pyridin‐2‐yl) and compound 2 containing aryl = 2‐ or 4‐hydroxyphenyl groups, with MIC values between 170 and 408 μM. Compound 2 containing OMe, H, F, Cl, Br, CN, and NO2 substituents and compound 3 (heteroaryl = furan‐2‐yl, thien‐2‐yl, pyrrol‐2‐yl, imidazol‐2‐yl, pyridin‐3‐yl, and pyridin‐4‐yl) were all inactive. Clearly, there is no correlation of activity with the electronic effects of the substituents. The activities suggest different modes of biological action of the compounds having nitro‐heteroaryl groups, on the one hand, and the 2‐hydroxyphenyl or pyridin‐2‐yl substituents, on the other hand. Compounds having 2‐ or 4‐hydroxyphenyl, 2‐hydroxy‐5‐nitrophenyl, or 4‐hydroxy‐3‐chlorophenyl were less cytotoxic than ethambutol. It is important to notice that compound 3 (aryl = 5‐NO2‐furan‐2‐yl) exhibited a promising therapeutic index (TI = 1093.90), with a value 4.4 less than that of ethambutol. Compounds 2 and 3 exist in DMSO or MeOD solutions as mixtures of EC(O)N/ECN and ZC(O)N/ECN conformers.

Synthesis and Antitumoral Evaluation of 7-chloro-4-quinolinylhydrazones Derivatives

A series of twenty-one 7-chloro-4-quinolinylhydrazones derivatives (3a-u) have been synthesized and evaluated for their cytotoxic potential against three cancer cell lines using MTT assay. The compounds 3b, 3e, 3f, 3h, 3j, 3n, 3r and 3u displayed more than 90% of growth inhibition (GI) and they were selected for in vitro anticancer activities evaluation against four human cancer cell lines. These results were expressed as the concentrations that induce 50% inhibition of cell growth (IC50) in μg/mL. Considering that, compounds 3b, 3e, 3h, 3n, 3r and 3u exhibited good cytotoxic activity against at least three cancer cell lines (0.7967-4.200 μg/mL). In general, we observed that the presence of electron-withdrawing groups in the benzene ring is important for the anticancer activity in this series, such as fluorine (3h), chlorine (3b) amd bromine (3e) groups in meta position and nitro group (3r) in para position. These derivatives could be considered interesting start points to develop a new anticancer drug and confirm the potential of chloroquine derivatives as lead compounds in anticancer drug discovery.

In vitro anti-mycobacterial activity of (E)-N´-(monosubstituted-benzylidene) isonicotinohydrazide derivatives against isoniazid-resistant strains

A series of twenty-three N-acylhydrazones derived from isoniazid (INH 1-23) have been evaluated for their in vitro antibacterial activity against INH- susceptible strain of M. tuberculosis (RG500) and three INH-resistant clinical isolates (RG102, RG103 and RG113). In general, derivatives 4, 14, 15 and 16 (MIC=1.92, 1.96, 1.96 and 1.86 µM, respectively) showed relevant activities against RG500 strain, while the derivative 13 (MIC=0.98 µM) was more active than INH (MIC=1.14 µM). However, these derivatives were inactive against RGH102, which displays a mutation in the coding region of inhA. These results suggest that the activities of these compounds depend on the inhibition of this enzyme. However, the possibility of other mechanisms of action cannot be excluded, since compounds 2, 4, 6, 7, 12–17, 19, 21 and 23 showed good activities against katG-resistant strain RGH103, being more than 10-fold more active than INH.

Structures of a co-crystal of tautomers of (E)-N-7-chloro-4-(2-methoxycinnamolyhydrazinyl)quinoline and a single tautomer of the 4-methoxy analogue

Abstract A crystal structure determination confirmed that the product from 7-chloroquinilin-4-ylhydrazine and 4-methoxycinnanamic acid had been isolated from MeOCH2CH2OH solution as [(E)-N′-7-chloro-4-(4-methoxycinnamolyhydrazinyl)quinoline, 1. In contrast, recrystallization of the 2-MeO derivative, 2, from the same solvent, produced a 1 : 1 co-crystalline mixture of two tautomers, namely (E)-N′-7-chloro-4-(2-methoxycinnaämolyhydrazinyl)quinoline and 7-chloro-4(1 H)quinolinone 3-(2-methoxycinnamoyl)hydrazone, molecules A and B, respectively. Molecules 1 and 2A have “L”-shapes and, in general, have very similar conformations, which differ from that of 2B, mainly arising from the rotation about the (O)C—N(N) bond within the linker unit between the quinolone and methoxyphenyl rings. In both 1 and 2, the 3-dimensional supramolecular arrangements involve strong N—H…N, N—H…O, C—H…O and C—H…π hydrogen bonds, while additionally in 2, there are π…π, C—Cl…π and C—H…Cl intermolecular interactions.

Thiourea Derivatives: A Promising Class Against HIV/TB Co-Infection

Nowadays, the Human Immunodeficiency Virus (HIV), which is the causative agent of Acquired Immune Deficiency Syndrome (AIDS), represents a serious public health problem. According to the World Health Organization (WHO), in 2009 there were 33.3 million people living with HIV worldwide, and more particularly in sub-Saharan Africa, where the overwhelming majority (67%) of cases appear. Furthermore, 2.6 million people have been recently infected with the virus in 2009, when HIV/AIDS was estimated to have caused 1.8 million deaths (United Nations Program on HIV/AIDS [UNAIDS], 2010). Due to the impairment of their immune system, HIV bearers are more susceptible to opportunistic infections, such as Tuberculosis (TB), which is a leading cause of HIV-related deaths worldwide. The risk for TB is 20-37-fold greater among HIV-infected individuals, depending on the status of the HIV epidemic. According to WHO, one-third of people living with HIV are infected with TB, and there was an estimate of 1.4 million new TB cases per year among said population. Moreover, one in four TB deaths occurs in HIV-positive patients, while TB was responsible for 23% of AIDS-related deaths (WHO, 2010a). This situation becomes especially alarming in view of the number of challenges in the control and management of TB in HIV-infected individuals, such as the difficulties to conclude a TB diagnosis, as well as the complexity involved in the treatment of HIV infection-related TB. Due to their great relevance to the subject matter of this work, the above factors will be emphasized in the next section.

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.

Variations in the intermolecular interactions in (E) benzaldehyde 7-chloro-1-methyl- 4H-quinolinyl-4-ylidene-hydrazone and seven halo derivatives

Abstract Eight crystal structures are reported here: substituted (E) benzaldehyde 7-chloro-1-methyl-4H-quinolinyl-4-ylidene-hydrazones, 1, [substituted benzaldehyde: XYC6H4CHO: X,Y=H,H; 2-F,H; 3-F,H; 4-F,H; 3-Cl,H; 4-Cl,H; 2-Br,H and 2,3-Cl2]. None of the molecules, 1, are overall planar: angles between the phenyl and and quinolinyl rings vary from <5°, for (1:X,Y=3-F,H; 4-F,H; 3-Cl,H and 2,3-Cl2) to 15–16° for (1: X,Y=H,H and 4-Cl,H). The supramolecular arrangements in the parent compound (1: X=Y=H) are generated solely from C–Z···π (Z=H and Cl) interactions, while the supramolecular arrangements for each of the halo derivatives arise from combinations of π···π and some of C–Z···π (Z=H, F, Cl) and C–H···Z (Z=N, F, Cl) intermolecular interactions: in each case different assemblies result. While there are possibilities for π(quin)···π(quin), π(quin)···π(phen) and π(phen)···π(phen) interactions [quin and phen refer to the quinolinyl and phenyl moieties], only compounds (1: X,Y=2,3-Cl2) and (1: X,Y=4-Cl,H) exhibit all three, (1: X,Y=2-Br,H) just π(quin)···π(quin) of the three, and in the others two of the three. All the halo derivatives exhibit π(quin)···π(quin) interactions. It is argued that steric hindrance between molecules, generated by the halo substituents, prevents the halo derivatives from adopting the packing arrangements of the parent compound, (1: X,Y=H,H). As there appears to be no reason, steric or otherwise, why compound (1: X,Y=H,H) cannot utiilize π···π interactions, it is apparent that the packing of molecules via the C–Y···π interactions is the most stable.

Pyrazinamide: An Essential Drug in the Tuberculosis Treatment

Pyrazinamide (PZA) is an important drug used against tuberculosis that helped to decrease the time of treatment from twelve to six months. The main action of this drug is the elimination of dormant bacilli, which are responsible for the emergence of resistant strains. However, few analogs have been synthesized with the purpose to explore and develop new compounds more effective and selective against M. tuberculosis. In this context, this review aims to highlight the importance of PZA in the treatment of tuberculosis as well as the development of new substances based on this drug with potential antimycobacterial activities.

Sodium Chlorite (NaClO2): an Important Reagent in Alcohol and Aldehyde Oxidation and its Application in Total Synthesis of Natural Products

Abstract The oxidation of alcohols is a fundamental transformation in organic synthesis and a large number of reagents have been developed for this purpose. In spite of the different methodologies, the modern organic synthesis still requires more efficient oxidant reagents. In this context, sodium chlorite (NaClO2) has emerged as the chosen reagent. The aim of this review is to highlight sodium chlorite oxidation due to the significance of this reagent nowadays as a very important procedure in the synthesis of natural products and derivatives, accomplished from 2005 to 2010.Abstract The oxidation of alcohols is a fundamental transformation in organic synthesis and a large number of reagents have been developed for this purpose. In spite of the different methodologies, the modern organic synthesis still requires more efficient oxidant reagents. In this context, sodium chlorite (NaClO2) has emerged as the chosen reagent. The aim of this review is to highlight sodium chlorite oxidation due to the significance of this reagent nowadays as a very important procedure in the synthesis of natural products and derivatives, accomplished from 2005 to 2010.