Claudia R. B. Gomes

Chemistry and Biological Activities of 1,3-Thiazolidin-4-ones

Abstract: 1,3-Thiazolidin-4-ones are an important group of heterocyclic compounds that are used in the field of medicinal chemistry. The utility of 1,3-thiazolidin-4-ones as synthons for various biological compounds has given impetus to these studies. In recent years, 1,3-thiazoldin-4-ones have been among the most extensively studied compounds. This review aims to review the work reported on the chemistry and biological activities of 1,3-thiazolidin-4-ones during the past few years. INTRODUCTION There are numerous biologically active molecules with five-membered rings, containing two hetero atoms. Thiazolidinone is an important scaffold known to be associated with several biological activities. A comprehensive review has been written on 4-thiazo-lidinones in 1981 [1]. 1,3-Thiazolidin-4-ones are heterocycles that have an atom of sul-fur at position 1, an atom of nitrogen at position 3 and a carbonyl group at position 4 (Fig. 1 ). Substituents in the 2-,3-, and 5-position may be varied, but in this review we focused only modifications in the positions 2 and 3. Numerous methods for the synthesis of thia-zolidinones and also their diverse reactions offer enormous scope in the field of medicinal chemistry. We present here the chemistry and biological properties of this heterocyclic ring since 2000. wave dielectric heating for the preparation of a small library of 1,3-1

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).

Efficient sonochemical synthesis of thiazolidinones from piperonilamine

An efficient multicomponent reaction of arenealdehydes, mercaptoacetic acid and piperonilamine under ultrasound irradiation to afford 2-aryl-3-(piperonylmethyl)-1,3-thiazolidin-4-ones is reported. Applying this methodology, eleven heterocycles were synthesized and isolated in good yields after short reaction times.

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 anti-mycobacterial activity of novel amino alcohol derivatives

Thirteen new hydroxyethylamines have been synthesized from reactions of (2S,3S)Boc-phenylalanine epoxide, piperonylamine and arenesulfonyl chlorides in good yields. These compounds 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. Two amino alcohols displayed significant activity when compared with first line drug ethambutol (EMB). Therefore this class of compounds could be a good starting point to develop new lead compounds in the treatment of tuberculosis.

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.

Perspectives on the Development of Novel Potentially Active Quinolones Against Tuberculosis and Cancer

Quinolones and its derivatives comprise an important group of heterocyclic compounds that exhibit a wide range of pharmacological properties such as antibacterial, antitumor, antiviral, anti-ischemic, antiparasitic and anxiolytic. Persistent efforts have been made over the years to develop novel congeners with superior biological activities and minimal potential for undesirable side-effects. The present review aims to highlight some recent discoveries on the development of novel quinolone-based compounds with potential antitubercular and anticancer activity.

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.