Gevanio Bezerra de Oliveira Filho

Structural investigation of anti-Trypanosoma cruzi 2-iminothiazolidin-4-ones allows the identification of agents with efficacy in infected mice.

We modified the thiazolidinic ring at positions N3, C4, and C5, yielding compounds 6-24. Compounds with a phenyl at position N3, 15-19, 22-24, exhibited better inhibitory properties for cruzain and against the parasite than 2-iminothiazolidin-4-one 5. We were able to identify one high-efficacy trypanocidal compound, 2-minothiazolidin-4-one 18, which inhibited the activity of cruzain and the proliferation of epimastigotes and was cidal for trypomastigotes but was not toxic for splenocytes. Having located some of the structural determinants of the trypanocidal properties, we subsequently wished to determine if the exchange of the thiazolidine for a thiazole ring leaves the functional properties unaffected. We therefore tested thiazoles 26-45 and observed that they did not inhibit cruzain, but they exhibited trypanocidal effects. Parasite development was severely impaired when treated with 18, thus reinforcing the notion that this class of heterocycles can lead to useful cidal agents for Chagas disease.

Structural design, synthesis and pharmacological evaluation of 4-thiazolidinones against Trypanosoma cruzi

Chagas disease is an infection caused by protozoan Trypanosoma cruzi, which affects approximately 8-10million people worldwide. Benznidazole is the only drug approved for treatment during the acute and asymptomatic chronic phases of Chagas disease; however, it has poor efficacy during the symptomatic chronic phase. Therefore, the development of new pharmaceuticals is needed. Here, we employed the bioisosterism to modify a potent antiparasitic and cruzain-inhibitor aryl thiosemicarbazone (4) into 4-thiazolidinones (7-21). Compounds (7-21) were prepared by using a straightforward synthesis and enabled good to excellent yields. As a chemical elucidation tool, X-ray diffraction of compound (10) revealed the geometry and conformation of this class compounds. The screening against cruzain showed that 4-thiazolidinones were less active than thiosemicarbazone (4). However, the antiparasitic activity in Y strain trypomastigotes and host cell cytotoxicity in J774 macrophages revealed that compounds (10 and 18-21) are stronger and more selective antiparasitic agents than thiosemicarbazone (4). Specifically, compounds (18-20), which carry a phenyl at position N3 of heterocyclic ring, were the most active ones, suggesting that this is a structural determinant for activity. In infected macrophages, compounds (18-20) reduced intracellular amastigotes, whereas Benznidazole did not. In T. cruzi-infected mice treated orally with 100mg/kg of compound (20), a decreased of parasitemia was observed. In conclusion, we demonstrated that the conversation of thiosemicarbazones into 4-thiazolidinones retains pharmacological property while enhances selectivity.

Design, synthesis and structure-activity relationship of phthalimides endowed with dual antiproliferative and immunomodulatory activities

The present work reports the synthesis and evaluation of the antitumour and immunomodulatory properties of new phthalimides derivatives designed to explore molecular hybridization and bioisosterism approaches between thalidomide, thiosemicarbazone, thiazolidinone and thiazole series. Twenty-seven new molecules were assessed for their immunosuppressive effect toward TNFα, IFNγ, IL-2 and IL-6 production and antiproliferative activity. The best activity profile was observed for the (6a-f) series, which presents phthalyl and thiazolidinone groups.

Phthaloyl amino acids as anti-inflammatory and immunomodulatory prototypes

A series of phthalimide analogs were synthesized by derivatization of phthalic anhydride, a highly toxic substance, using a “one pot” condensation reaction to α-amino acids. All phthaloyl amino acid derivatives presented anti-oral inflammatory activity, but compounds 2e and 2g were found to possess the best activities comparable to thalidomide. Most of the compounds effectively suppressed nitric oxide production in murine cells stimulated with lipopolysaccharide. N-phthaloyl amino acids did not exhibit any significant cytotoxicity in vitro when tested against tumor cells as well as a spleen cell culture of BALB/c mice. Compounds 2a, 2g, and 2h were able to inhibit TNF-α and IL-1β production by macrophages. At the same concentration, thalidomide did not exhibit significant inhibitory activity.Graphical Abstract[The pharmacological evaluation of eight N-phthaloyl amino acids 2a–h, including their anti-inflammatory and cytotoxic effects and nitric oxide, TNF-α, and IL-1β production, is described.]

Compound profiling and 3D-QSAR studies of hydrazone derivatives with activity against intracellular Trypanosoma cruzi.

Chagas disease is a tropical disease caused by the parasite Trypanosoma cruzi, which is endemic in Central and South America. Few treatments are available with effectiveness limited to the early (acute) stage of disease, significant toxicity and widespread drug resistance. In this work we report the outcome of a HTS-ready assay chemical library screen to identify novel, nontoxic, small-molecule inhibitors of T. cruzi. We have selected 50 compounds that possess hydrazone as a common group. The compounds were screened using recombinant T. cruzi (Tulahuen strain) expressing beta-galactosidase. A 3D quantitative structure-activity relationship (QSAR) analysis was performed using descriptors calculated from comparative molecular field analysis (CoMFA). Our findings show that of the fifty selected hydrazones, compounds LpQM-19, 28 and 31 displayed the highest activity against T. cruzi, leading to a selectivity index (SI) of 20-fold. The 3D-QSAR analysis indicates that a particular electrostatic arrangement, where electron-deficient atoms are aligned along the molecule main axis positively correlates with compound biological activity. These results provide new candidate molecules for the development of treatments against Chagas disease.

Novel phthalimide derivatives with TNF-α and IL-1β expression inhibitory and apoptotic inducing properties

Modulation of the immune system is an emerging concept in the control of tumor growth. Bearing in mind the pharmacological properties of thalidomide and its phthalimide derivatives, we describe here the structural design, synthesis and pharmacological evaluation of N-acylhydrazones derived from phthalimide. The ability of these N-acylhydrazones in inhibiting the secretion of TNF-α in stimulated cells as well as in inhibiting the transcription of the TNF-α gene was evaluated. We identified N-acylhydrazones 6b and 9c, which substantially impaired TNF-α secretion, expression and reduced IL-1β production similar to thalidomide or Revlimid. N-Acylhydrazone 9c was also able to induce apoptosis in Jurkat cells, however it does not have either antiproliferative properties or cytotoxicity for mouse splenocytes. Beyond that, we have assayed the ability of these compounds to induce cell death and a number of them are able to induce apoptosis.

Structural improvement of new thiazolidinones compounds with antinociceptive activity in experimental chemotherapy-induced painful neuropathy

Chemotherapy‐induced neuropathy is a disabling pain condition resulting from chemotherapy for cancers. Up to now, no drug is available to cure chemotherapy‐induced neuropathy. In the present study, we describe the structural design, synthesis, chemical and pharmacological characterization of 15 thiazolidinones, a class of potential analgesic compounds. The synthesis of new thiazolidinones was achieved by using the thiazolidinone heterocyclic as main structural pharmacophoric group and varying the substituents attached to the phenyl near to the iminic bond. The analgesic potential of the compounds was investigated in a mice model of oxaliplatin‐induced neuropathic pain, using von Frey, rota‐rod and open‐field tests. Except for compound 14, these thiazolidinones exhibited antinociceptive property without causing motor impairment. Thiazolidinones 12, 15 and 16 displayed a dose‐dependent antinociceptive effect, with similar efficacy and enhanced potency than gabapentin, the gold standard drug used for neuropathic pain. In addition, the antinociceptive activity of 16 lasted longer than gabapentin. The antinociceptive effect of thiazolidinones was prevented by GW9662, a PPARγ antagonist. The main antinociceptive compounds exhibited positive Lipinskis index, predicting their oral bioavailability. In conclusion, the structural design performed here led to the identification of new compounds endowed with potent antinociceptive activity, potentially useful to treat chemotherapy‐induced neuropathic pain.

Phthalimido-thiazole as privileged scaffold: activity against immature and adult worms of Schistosoma mansoni

AbstractPhthalimide, 1,3-thiazole, and thiazolidinone cores are considered privileged scaffolds and represent an attractive starting point to design new bioactive compounds for neglected tropical disease (NTD). Schistosomiasis is a NTD, caused by Schistosoma worms which praziquantel (PZQ) is the only drug used to treat humans, but the decrease in the effect after treatment has been reported. Recently, some phthalimide-thiazole derivatives exhibited in vitro antischistosomal activity against adult worms with significant ultrastructural changes and a lower cytotoxic effect on splenocytes. This new biological phthalimido-thiazole profile has motivated us to evaluate a new generation of such molecules in immature and adult worms. Thus, a phthalimido-thiazolidinone derivative, (3c), and three phthalimido-thiazoles (6c, 7a, and 7h) were evaluated concerning their in vitro activity on schistosomulae and adult worms. The results showed that these compounds brought a significant reduction on the mortality, inhibited oviposition, and then induced mortality in immature and adult worms alike. According to scanning electron microscopy, the tegument was the principal target for 7a and 7h and revealed gradual damage to the tegument surface, inducing destruction and decomposition of the tegument in the same areas and exposition of subtegumental tissue and of muscle tissue. Furthermore, they caused less toxicity in splenocytes than PZQ. Compounds 7a and 7h revealed to possess promising activity against larval forms. According to the present study, the privileged structure phthalimido-thiazoles act as a molecular framework that has antischistosomal activity and most form the basis to the next pre-clinical tests. Graphical abstract