Marcele Moreth

Synthesis and antimalarial activity of hydroxyethylpiperazine derivatives

The antimalarial activity of hydroxyethylpiperazine derivatives, synthesized from the reaction of (2S,3S)Boc-phenylalanine epoxide with benzylpiperazines in good yields (76-96%), has been evaluated in vitro against the Plasmodium falciparum W2 clone (chloroquine resistant). The results show that some compounds have moderate activity against this parasite and none of the active compounds showed cytotoxicity at high concentration (100 microg/ml).

Synthesis, antimalarial evaluation and molecular modeling studies of hydroxyethylpiperazines, potential aspartyl protease inhibitors, Part 2.

The antimalarial acitivity of hydroxyethylamines, synthesized from the reaction of intermediated hydroxyethypiperazines with benzenesulfonyl chlorides or benzoyl chlorides, has been evaluated in vitro against a W2 Plasmodium falciparum clone. Some of the nineteen tested derivatives showed a significant activity in vitro, thus turning into a promising new class of antimalarials. In addition, a molecular modeling study of the most active derivative (5l) was performed and its most probable binding modes within plasmepsin II enzyme were identified.

Microwave-Assisted Synthesis of 1,3-Thiazolidin-4-ones and 2-Aryl-1,3-oxathiolan-5-ones

A microwave-enhanced, rapid, three-component one-pot condensation method has been developed for the synthesis of 1,3-thiazolidin-4-ones using toluene in open vessels at atmospheric pressure. Applying this methodology, eleven 1,3-oxathiolan-5-ones were also synthesized in good yields. Thiazolidinones belong to an important group of heterocyclic compounds possessing diverse biological activities such as insecticidal, anticonvulsant, tuberculostatic, antiinflammatory, antiviral, etc. [1]. The anti-HIV biological activity of thiazolidinones has been associated with the ability to assume “butterfly-like” conformation [2-4]. These compounds have been previously prepared from three components (an aldehyde, an amine and mercapto acetic acid), by various oneand two-step syntheses [1]. Such reactions have also been carried out using microwave irradiation [5,6]. The reactions proceed by initial imine formation, which undergoes attack by the sulfur nucleophile, followed by intramolecular cyclization on elimination of water. The most common protocol to remove the water is by azeotropic distillation. Recently we published the formation of 4thiazolidinones by cyclocondensation reactions of an aminoacid, arenealdehydes and mercaptoacetic acid in moderate to good yields [7-9]. In the current work, we studied the formation of these heterocycles using microwave irratiation. *Address correspondence to this author at the Instituto de Tecnologia em Farmacos – Farmanguinhos FIOCRUZ. R. Sizenando Nabuco 100, Manguinhos, 21041-250, Rio de Janeiro-RJ, Brazil; E-mail: wjcunico@far.fiocruz.br Microwave irradiation is an alternative heating method based on the ability of compounds to transform electromagnetic energy into heat. This method, which can increase chemical reaction rates, yields and can form cleaner products, can be sucessfully applied in pharmaceutical chemistry [10,11]. Considering that MW irradiation using commercial domestic ovens has been recently used to accelerate organic reactions [12-14], we have compared the results of formation of 1,3-thiazolidin-4-ones and 1,3-oxathiolan-5-ones performed by the microwave-assited method and conventional procedures. The 1,3-thiazolidin-4-ones were synthesized from the reaction of arenealdehydes and valine with an excess of mercaptoacetic acid, using toluene in microwave oven, for six minutes (Scheme 1). When the nitrobenzaldehydes were used, the major products were 2-aryl-3-benzyl-1,3thiazolidin-4-ones 2a-c in excellent yields (Table 1). However, when 4-methoxyben-zaldehyde (entry 5) and 4fluorobenzaldehyde (entry 4) were used as precursors, a mixture of heterocycles 2, 3 and 4 was detected by GC and their separation was difficult due to similar retention times as stated in previous works (Table 1) [7,8]. CHO

Synthesis and Antimycobacterial Activity of 2-aryl-3-(arylmethyl)-1,3- thiazolidin-4-ones

Fifteen new heterocyclic thiazolidinones have been synthesized from one-pot reactions of piperonylamine, are- nealdehydes and mercaptoacetic acid. These compounds plus ten 2-aryl-3-(benzyl)-1,3-thiazolidin-4-ones which had been previously synthesized, were evaluated as antibacterial agents against Mycobacterium tuberculosis H37Rv using the Alamar Blue susceptibility test and their activity expressed as the minimum inhibitory concentration (MIC) in μg/mL. Six of the series exhibited modest activity when compared to the first line drugs such as isoniazid (INH) and rifampicin (RIP). Therefore this class of compounds could be a good starting point to develop new lead compounds in the treatment of multi-drug resistant tuberculosis.

Synthesis and Antimycobacterial Activity of Novel Amino Alcohols Containing Central Core of the Anti-HIV Drugs Lopinavir and Ritonavir

Eleven new amino alcohol derivatives have been synthesized from reactions of lopinavir intermediate and heteroaromatic aldehyde in good yields. These compounds, the antiretrovirals (lopinavir and ritonavir) and lopinavir key intermediate were evaluated as antibacterial agents against Mycobacterium tuberculosis H37Rv using the Alamar Blue susceptibility test and their activity expressed as the minimum inhibitory concentration (MIC) in μm. Ten amino alcohols evaluated displayed significant activity (MIC between 6.15 and 108.4 μm) when compared to first‐line drug ethambutol (MIC = 15.9 μm). Three of them showed more activity than ethambutol (MIC = 6.15; 6.21 and 13.4 μm). The appreciable activity of these compounds can be considered an important finding for the rational design of new leads for anti‐TB compounds.

Structures of three (2R,3S)-4-(arylmethyl)-1-(4-phenyl-3-amino-2-hydroxy-butyl)-piperazine derivatives, potential anti-malarial agents

Abstract Selected (2R,3S)-4-(arylmethyl)-1-(4-phenyl-3-substituted-amino-2-hydroxybutyl)piperazine derivatives have anti-malarial activity. The crystal structures of active tert-butyl (2S,3R)-4-(4-benzo[d][1,3]dioxol-5-ylmethyl)piperazin-1-yl)-3-hydroxy-1-phenylbutan-2-ylcarbamate, (1), nonactive (2S,3R)-4-(4-nitrobenzyl)piperazin-1-yl)-3-hydroxy-1-phenyl-2-(4-toluenesulfonamido)butane, (2), and the active dihydrated salt, (2S,3R)-4-(4-(benzo[d]-[1,3]dioxol-5-ylmeäthyl)piperazin-1-yl)-3-hydroxy-1-phenyl-2-(4-toluenesulfonamido)butane.dihydrogen chloride, (3) are reported. Biological studies indicated the importance of the OH, the benzyl group and the methylene substituents, at the piperazinyl nitrogens, for generating activity. The bond distances in 1 and 2 and the two independent dications of 3, involving these units, do not correlate with activities. However, the molecular conformation adopted by 2, was different from that in 1 and the dications of 3. Both 1 and 2 possess O(1)—H(1)—O(1) and N—HN—O intermolecular H-bonds: in both cases, the O—H—O hydrogen bonds involve the hydroxyl oxygen atom, while the N—H—O interaction for 1 involves the carbonyl oxygen and that for 2, a sulfonyl oxygen. The dications of 3 are not directly connected by H-bonds, but each independent dication is linked via chloride anions and water molecules into chains. Three-dimensional networks are obtained for 1–3 from intermolecular C—H-π and or intermolecular C—H—O and C—H-π interactions.

Syntheses and Antimycobacterial Activities of [(2S,3R)-2-(Amino)-4- (Arenesulfonamido)-3-Hydroxy-1-Phenylbutane Derivatives

The syntheses of hydroxyethylsulfonamides, (2S,3R)-tert-butyl N-[4-(N-benzyl-4-R-phenylsulfonamido)-3- hydroxy-1-phenylbutan-2-yl]carbamates and (5) (2S,3R)-2-amino-4-[N-benzyl-4-R-benzenesulfonamido]-3-hydroxy-1- phenylbutane hydrochlorides (6), derived from (2S,3S)-Boc-phenylalanine epoxide, are reported. None of the compounds, containing the Boc group, showed activity against M. tuberculosis ATTC 27294, while compounds 6 did, with the most active compounds having R = p-Cl, p-Br and p-Me. Results indicate that the presence of a free amino group at C2 and the sulphonamide moiety are important for biological activity. The antimycobacterial activity of compounds 6 correlated well with the calculated lipophilicities, but not with the electronic effects of the substituents, R. All compounds 6 were highly cytotoxic against the hepatoma cell lineage Hep G2 A16. The X-ray crystal structure of compound [(6: R = Me).H2O] is also reported. In the propeller-like conformation adopted by the cation, the amino and hydroxy groups have a cis arrangement, and thus are suitably placed to form 5- membered chelates.

Synthesis and In Vivo Antimalarial Evaluation of Novel Hydroxyethylamine Derivatives

A series of hydroxyethylamines has been synthesized from the reaction of (2S,3S )Boc-phenylalanine epoxide with alkyl amines in good yields and evaluated for their in vivo antimalarial activity in mice. Compound 4g presented better activity then the reference artesunate in percentage of inhibition of parasitemia in treated P. berghei-infected mice and compare to the activity of artesunate in the survival of mice 14 days after infection. In addiction, no hemolytic activity was found, which supports that inhibition of parasitemia is due to antimalarial activity. The compound 4g inhibited the differentiation to schizonts suggesting that parasite metabolism is a possible target of 4g. These results indicate that this class of compound possesses promising perspectives for the development of new antimalarial drugs.

Oral effectiveness of PMIC4, a novel hydroxyethylpiperazine analogue, in Leishmania amazonensis

Graphical abstract

(2S,3R)-tert-Butyl N-[4-(N-benzyl-4-fluoro-benzene-sulfonamido)-3-hy-droxy-1-phenyl-butan-2-yl]carbamate.

In the title molecule, C28H33FN2O5S, the mean plane about the tertiary amine group (sum of the angles subtended at the sp 2-hybridized N atom = 359.7°) forms a dihedral angle of 16.66 (6)° with the phenyl ring adjacent to the carbamate group. The sulfonamide benzene ring and the hydroxy group lie to either side of the C2NS plane, whereas the benzylphenyl (connected to the N atom) and carbamate substituents lie to the other side. Supramolecular layers propagating in the ac plane are found in the crystal, linked by hydroxy–sulfonamide O—H⋯O and carbamate–carbamate N—H⋯O hydrogen bonds along with C—H⋯O and C—H⋯π interactions.