Mônica M. Bastos

The clinically approved antiviral drug sofosbuvir inhibits Zika virus replication.

Zika virus (ZIKV) is a member of the Flaviviridae family, along with other agents of clinical significance such as dengue (DENV) and hepatitis C (HCV) viruses. Since ZIKV causes neurological disorders during fetal development and in adulthood, antiviral drugs are necessary. Sofosbuvir is clinically approved for use against HCV and targets the protein that is most conserved among the members of the Flaviviridae family, the viral RNA polymerase. Indeed, we found that sofosbuvir inhibits ZIKV RNA polymerase, targeting conserved amino acid residues. Sofosbuvir inhibited ZIKV replication in different cellular systems, such as hepatoma (Huh-7) cells, neuroblastoma (SH-Sy5y) cells, neural stem cells (NSC) and brain organoids. In addition to the direct inhibition of the viral RNA polymerase, we observed that sofosbuvir also induced an increase in A-to-G mutations in the viral genome. Together, our data highlight a potential secondary use of sofosbuvir, an anti-HCV drug, against ZIKV.

Design, Synthesis and Pharmacological Evaluation of HIV-1 Reverse Transcriptase Inhibition of New Indolin-2-Ones

The design, synthesis and anti HIV-1 replication inhibition of 3-(cyclopropylethynyl)-3-hydroxy-indolin-2-ones, analogues of efavirenz (Sustivatrade mark), are described. Different substituted isatins were used to generate final products that contain pharmacophoric features for RT inhibition, such as the oxoindole and cyclopropylethynyl groups. The suitability of the indolin-2-one ring in the planned compounds in replacement to the benzoxazinone ring of efavirenz was proven, since compound 15 presented a greater activity than efavirenz against HIV-1 replication and was not significantly cytotoxic.

New trifluoromethyl triazolopyrimidines as anti-Plasmodium falciparum agents.

According to the World Health Organization, half of the World’s population, approximately 3.3 billion people, is at risk for developing malaria. Nearly 700,000 deaths each year are associated with the disease. Control of the disease in humans still relies on chemotherapy. Drug resistance is a limiting factor, and the search for new drugs is important. We have designed and synthesized new 2-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyrimidine derivatives based on bioisosteric replacement of functional groups on the anti-malarial compounds mefloquine and amodiaquine. This approach enabled us to investigate the impact of: (i) ring bioisosteric replacement; (ii) a CF3 group substituted at the 2-position of the [1,2,4]triazolo[1,5-a]pyrimidine scaffold and (iii) a range of amines as substituents at the 7-position of the of heterocyclic ring; on in vitro activity against Plasmodium falciparum. According to docking simulations, the synthesized compounds are able to interact with P. falciparum dihydroorotate dehydrogenase (PfDHODH) through strong hydrogen bonds. The presence of a trifluoromethyl group at the 2-position of the [1,2,4]triazolo[1,5-a]pyrimidine ring led to increased drug activity. Thirteen compounds were found to be active, with IC50 values ranging from 0.023 to 20 µM in the anti-HRP2 and hypoxanthine assays. The selectivity index (SI) of the most active derivatives 5, 8, 11 and 16 was found to vary from 1,003 to 18,478.

Novel Selective Inhibitor of Leishmania (Leishmania) amazonensis Arginase

Arginase is a glycosomal enzyme in Leishmania that is involved in polyamine and trypanothione biosynthesis. The central role of arginase in Leishmania (Leishmania) amazonensis was demonstrated by the generation of two mutants: one with an arginase lacking the glycosomal addressing signal and one in which the arginase‐coding gene was knocked out. Both of these mutants exhibited decreased infectivity. Thus, arginase seems to be a potential drug target for Leishmania treatment. In an attempt to search for arginase inhibitors, 29 derivatives of the [1,2,4]triazolo[1,5‐a]pyrimidine system were tested against Leishmania (Leishmania) amazonensis arginase in vitro. The [1,2,4]triazolo[1,5‐a]pyrimidine scaffold containing R1 = CF3 exhibited greater activity against the arginase rather than when the substituent R1 = CH3 in the 2‐position. The novel compound 2‐(5‐methyl‐2‐(trifluoromethyl)‐[1,2,4]triazolo[1,5‐a]pyrimidin‐7‐yl)hydrazinecarbothioamide (30) was the most potent, inhibiting arginase by a non‐competitive mechanism, with the Ki and IC50 values for arginase inhibition estimated to be 17 ± 1 μm and 16.5 ± 0.5 μm, respectively. These results can guide the development of new drugs against leishmaniasis based on [1,2,4]triazolo[1,5‐a]pyrimidine derivatives targeting the arginase enzyme.

The clinically approved antiviral drug sofosbuvir impairs Brazilian zika virus replication

Zika virus (ZIKV) is a member of Flaviviridae family, as other agents of clinical significance, such as dengue (DENV) and hepatitis C (HCV) viruses. ZIKV spread from Africa to Pacific and South American territories, emerging as an etiological pathogen of neurological disorders, during fetal development and in adulthood. Therefore, antiviral drugs able to inhibit ZIKV replication are necessary. Broad spectrum antivirals, such as interferon, ribavirin and favipiravir, are harmful for pregnant animal models and women. The clinically approved uridine nucleotide analog anti-HCV drug, sofosbuvir, has not been affiliated to teratogenicity. Sofosbuvir target the most conserved protein over the members of the Flaviviridae family, the viral RNA polymerase. We thus studied ZIKV susceptibility to sofosbovir. We initially characterized a Brazilian ZIKV strain for use in experimental assays. Sofosbuvir inhibits the Brazilian ZIKV replication in a dose-dependent manner, both in BHK-21 cells and SH-Sy5y, by targeting ZIKV RNA polymerase activity, with the involvement of conserved amino acid residues over the members of Flaviviridae family. The identification of clinically approved antiviral drugs endowed with anti-ZIKV could reduce the time frame in pre-clinical development. Altogether, our data indicates that sofosbuvir chemical structure is endowed with anti-ZIKV activity.

New pentasubstituted pyrrole hybrid atorvastatin–quinoline derivatives with antiplasmodial activity

Cerebral malaria is caused by Plasmodium falciparum. Atorvastatin (AVA) is a pentasubstituted pyrrole, which has been tested as an adjuvant in the treatment of cerebral malaria. Herein, a new class of hybrids of AVA and aminoquinolines (primaquine and chloroquine derivatives) has been synthesized. The quinolinic moiety was connected to the pentasubstituted pyrrole from AVA by a linker group (CH2)n=2-4 units. The activity of the compounds increased with the size of the carbons chain. Compound with n=4 and 7-chloroquinolinyl has displayed better activity (IC50=0.40 μM) than chloroquine. The primaquine derivative showed IC50=1.41 μM, being less toxic and more active than primaquine.

Efavirenz a nonnucleoside reverse transcriptase inhibitor of first-generation: Approaches based on its medicinal chemistry.

Acquired immunodeficiency syndrome (AIDS) is a disease caused by human immunodeficiency virus (HIV) that affects individuals on all continents. In 1987, the antiretroviral therapy began increasing survival rates and improving the quality of life for patients. Efavirenz (EFV) is a drug widely used in the treatment of HIV-AIDS since 1998. Belonging to a class of nonnucleoside reverse transcriptase inhibitors (NNRTI), it directly blocks the action of the enzyme and consequently the multiplication of the virus. Although EFV has provided excellent results in reducing viral load, cases of resistance associated with adverse effects have led to the search to find new analogs of this drug. Although many researchers are involved in this quest, curiously there is still no clinical substitute for EFV. To develop a second-generation version of EFV, it is essential understand the structure-activity relationships of the derivative compounds. Thus, the aims of the present review are to compare EFV and its derivatives using medicinal chemistry and to describe the main synthetic routes.

Structures of 1-(substituted-phenyl)-4-hydroxymethyl-and -4-fluoromethyl-1,2,3-triazoles

Abstract The crystal structures of 4-FCH2-1-(4-X-phenyl)-triazole (1: X = Cl, Br and CN) and 4-HOCH2-1-(4-X-phenyl)-triazole (2: X = Cl, Br and CN) are reported. Each of the pairs, (1: X = Cl) and (1: X = Br) and (2: X = Cl) and (2: X = Br), are isostructural. There are no strong intermolecular interactions in any of the compounds 1. Present in (1: X = CN), are C—H···N, C—H···F and C—H···π hydrogen bonds, and π···π stacking interactions, while in (2: X = Cl and Br) present are C—H···N, C—H···F and C—X···π, hydrogen bonds, with resulting different supramolecular arrays produced for the halo, on one hand, and cyano derivatives, on the other. The hydroxyl-triazole nitrogen interactions in 2 are the strongest intermolecular interactions present in 2. In the case of (2: X = Cl and Br), augmenting this strong O—H···N hydrogen bond with a weaker C—H···O hydrogen bond results in a [C(6)R22(10)] chain of molecules propagated head-to-tail along the b axis. In contrast, this strong O—H···N hydrogen bond in (2: X = CN), now augmented by C—H···N(cyano nitrogen), results in a chain of molecules, [C(19)R22(10)R22(10)]. Further weaker intermolecular interactions of the types, C—H···N and C—H···O hydrogen bonds and π···π stacking interactions for (2: X = CN), and of the types, C—H···O and C—X···π hydrogen bonds, and π···π stacking interactions for (2: X = Cl and Br) generate significantly different supramolecular arrays.

Yellow fever virus is susceptible to sofosbuvir both in vitro and in vivo

Yellow fever virus (YFV) is a member of the Flaviviridae family, that causes major mortality. In Brazil, YFV activity increased in the last years. It has been registered that sylvatic, instead of urban, yellow fever (YF) leads our contemporary public health concern. Low vaccinal coverage leaves the human population near the jangle vulnerable to the outbreak, making it necessary to identify therapeutic options. Repurposing of clinically approved antiviral drugs represents an alternative for such identification. Other Flaviviruses, such Zika (ZIKV) and dengue (DENV) viruses, are susceptible to Sofosbuvir, a clinically approved drug against hepatitis C virus (HCV). Moreover, sofosbuvir has a safety record on critically ill hepatic patients, making it an attractive option. Our data show that YFV RNA polymerase uses conserved amino acid resides for nucleotide binding to dock sofosbuvir. This drug inhibited YFV replication in different lineages of human hepatoma cells, Huh-7 and HepG2, with EC50 value of 4.8 µM. Sofosbuvir protected YFV-infected neonatal Swiss mice from mortality and weight loss. Our pre-clinical results indicate that sofosbuvir could represent an option against YFV.

Imatinib derivatives as inhibitors of K562 cells in chronic myeloid leukemia

Imatinib was the first representative of the class of Breakpoint cluster region-Abelson murine leukemia viral oncogene homolog (BCR-ABL) tyrosine kinase inhibitors used for the treatment of chronic myeloid leukemia. Second-generation and third-generation drugs have been introduced in this therapy, affording increased patient survival. However, all BCR-ABL tyrosine kinase inhibitors have been shown to induce resistance, necessitating a search for new therapeutic options. The sunitinib, another tyrosine kinase inhibitor used in the treatment of renal cell carcinoma and gastrointestinal stromal tumors is an isatin derivative. Isatin nucleus is highly versatile for the preparation of new substances, and several tyrosine kinase inhibitors examples have been obtained using it. This work aimed to design, synthesize, and biological evaluation of new compounds using the K562 cell line, which constitutively expresses the active BCR-ABL enzyme. Three new series of imatinib derivatives have been planned from the imatinib, and all have a phenylaminopyrimidine group as the main pharmacophore. Sunitinib was used as a structural prototype to planning the series 1 (8a–e) of hybrids between sunitinib and imatinib. Series 2 and 3 are 2-oxo-2-phenyacetamide and 2,2-difluoro-2-phenylacetamide derivatives, respectively. Isatins were used as the starting materials for all series. Compounds were synthesized using simple methodologies and were obtained in high purities. The compounds were tested against K562 cells, and four showed a reduction in cell viability, with EC50 values ranging from 0.37 to 2.02 μM, some of which are close to the imatinib standard (0.21 µM).