Synthesis and biological evaluation of isobavachalcone (IBC) and analogs as potential agents against tuberculosis

• Grant number: 18/15083-2
• Support Opportunities: Regular Research Grants
• Start date: July 01, 2019
• End date: June 30, 2021
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Luis Octávio Regasini
• Grantee: Luis Octávio Regasini
• Host Institution: Instituto de Biociências, Letras e Ciências Exatas (IBILCE). Universidade Estadual Paulista (UNESP). Campus de São José do Rio Preto. São José do Rio Preto , SP, Brazil

Abstract

Tuberculostatics are crucial drugs to for life expectancy, mainly to HIV-positive patients. Several reasons justify the need for new antimycobacterial, including high morbilitiy and mortality related to tuberculosis. The resurgence of multidrug resistant (MDR-TB) and extensively drug resistant (XDR-TB), typical morphophysiological features of Mycobacterium tuberculosis, as well as phenotypical forms (active and latent), also are challenge to discovery of tuberculostatics. Thus, efforts are necessary to discover and develop tuberculostatic with innovative structural and mechanistic patterns. The current project aims the synthesis and biological evaluation of isobavachalcone (IBC), a tri-hydroxylated and C-isoprenylated chalcone with potent and unexplored tuberculostatic activity. Three series of analogs of IBC will be synthesized. Series I, II and III will exhibit modifications on chalconic ring A, ring B and alpha, beta-unsaturated ketone, respectively. The synthetical strategy will include iodation and Suzuki coupling reactions (or Stille reaction and Heck reaction), allowing C-prenylation at carbon C-3' (ring A). The antimycobacterial potency will be determined against sensitive H37Rv and clinical isolates (MDR-TB and XDR-TB) strains., indicating Minimum Inhibitory Concentration (MIC) values. The n-octanol/water partition coefficient (log Po/w) will be performed by HPLC-DAD experiment, aiming to relate hydrophobicity and antimycobacterial activity of chalcones. The values of log Po/w and melting points of chalcones will be used in the prection of water-solubility (log S), by using of General Solubility Equation. Antimycobacterial compounds (MIC H37Rv < 10 uM) will be submitted to toxicity evaluations against eukaryotic cells, including murine macrophages (J774A.1), human pneumocytes (MRC-5) and human hepatocytes HepG2), stablishing selective index (IS - IC50 eukaryote/MIC H37Rv). Chalcones that exhibited SI (macrophage) > 10 will be selected to evaluation against intramacrophagic forms of Erdman M. tuberculosis. In addition, compound that activity against resistant clinical isolates will be submitted to inhibition assays of efflux pump of Mycobacterium smegmatis, as model with reduce biological risk. (AU)

Scientific publications

(19)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

POLAQUINI, CARLOS R.; MORAO, LUANA G.; NAZARE, ANA C.; TORREZAN, GUILHERME S.; DILARRI, GUILHERME; CAVALCA, LUCIA B.; CAMPOS, DEBORA L.; SILVA, ISABEL C.; PEREIRA, JESSE A.; SCHEFFERS, DIRK-JAN; et al. Antibacterial activity of 3,3 `-dihydroxycurcumin (DHC) is associated with membrane perturbation. BIOORGANIC CHEMISTRY, v. 90, n. SI, SEP 2019. (18/15083-2, 09/53989-4, 17/50216-0, 15/50162-2, 15/08089-6, 13/50367-8, 14/50880-0)

MORAO, LUANA G.; LORENZONI, ANDRE S. G.; CHAKRABORTY, PARICHITA; AYUSSO, GABRIELA M.; CAVALCA, LUCIA B.; SANTOS, MARIANA B.; MARQUES, BEATRIZ C.; DILARRI, GUILHERME; ZAMUNER, CAIO; REGASINI, LUIS O.; et al. Investigating the Modes of Action of the Antimicrobial Chalcones BC1 and T9A. Molecules, v. 25, n. 20, OCT 2020. (16/07108-0, 17/50216-0, 14/18577-5, 14/18330-0, 18/15083-2, 16/08084-7, 14/18719-4)

CURY SATOKATA, ALESSANDRA AKEMI; SOUZA, JONATHAN HENRIQUE; OLIVEIRA SILVA, LUANA LUIZA; SANTIAGO, MARIANA BRENTINI; RAMOS, SALVADOR BOCCALETTI; DE ASSIS, LETICIA RIBEIRO; THEODORO, REINALDO DOS SANTOS; RODRIGUES E OLIVEIRA, LIGIA; REGASINI, LUIS OCTAVIO; GOMES MARTINS, CARLOS HENRIQUE. Chalcones with potential antibacterial and antibiofilm activities against periodontopathogenic bacteria. Anaerobe, v. 76, p. 9-pg., 2022-08-01. (14/50926-0, 14/18330-0, 14/50880-0, 09/53989-4, 18/15083-2)

RAMOS, PAULO RICARDO PIMENTA DA SILVA; MOTTIN, MELINA; LIMA, CAROLINE SPRENGEL; ASSIS, LETICIA R.; DE OLIVEIRA, KETLLYN ZAGATO; MESQUITA, NATHALYA CRISTINA DE MORAES ROSO; CASSANI, NATASHA MARQUES; SANTOS, IGOR ANDRADE; BORBA, JOYCE VILLA VERDE BASTOS; FIAIA COSTA, VINICIUS ALEXANDRE; et al. Natural Compounds as Non-Nucleoside Inhibitors of Zika Virus Polymerase through Integration of In Silico and In Vitro Approaches. PHARMACEUTICALS, v. 15, n. 12, p. 17-pg., 2022-12-01. (14/18330-0, 19/01762-8, 13/07600-3, 18/15083-2, 20/12904-5)

POLAQUINI, CARLOS R.; MORAO, LUANA G.; NAZARE, ANA C.; TORREZAN, GUILHERME S.; DILARRI, GUILHERME; CAVALCA, LUCIA B.; CAMPOS, DEBORA L.; SILVA, ISABEL C.; PEREIRA, JESSE A.; SCHEFFERS, DIRK-JAN; et al. Antibacterial activity of 3,3 '-dihydroxycurcumin (DHC) is associated with membrane perturbation. BIOORGANIC CHEMISTRY, v. 90, p. 8-pg., 2019-09-01. (09/53989-4, 13/50367-8, 15/50162-2, 15/08089-6, 17/50216-0, 14/50880-0, 18/15083-2)

DOS SANTOS, MARIANA BASTOS; ANSELMO, DAIANE BERTHOLIN; DE OLIVEIRA, JESSICA GISLEINE; JARDIM-PERASSI, BRUNA V.; MONTEIRO, DIEGO ALVES; SILVA, GABRIEL; GOMES, ELENI; FACHIN, ANA LUCIA; MARINS, MOZART; PIRES DE CAMPOS ZUCCARI, DEBORA APARECIDA; et al. Antiproliferative activity and p53 upregulation effects of chalcones on human breast cancer cells. Journal of Enzyme Inhibition and Medicinal Chemistry, v. 34, n. 1, p. 1093-1099, JAN 1 2019. (18/15083-2, 14/18330-0)

LIMA, CAROLINE SPRENGEL; PEREIRA, MATHEUS HENRIQUE; GAINZA, YOUSMEL ALEMAN; HOSTE, HERVE; REGASINI, LUIS OCTAVIO; DE SOUZA CHAGAS, ANA CAROLINA. Anthelmintic effect of Pterogyne nitens (Fabaceae) on eggs and larvae of Haemonchus contortus: Analyses of structure-activity relationships based on phenolic compounds. INDUSTRIAL CROPS AND PRODUCTS, v. 164, JUN 2021. (18/15083-2, 14/18330-0)

POLAQUINI, CARLOS R.; MARQUES, BEATRIZ C.; AYUSSO, GABRIELA M.; MORAO, LUANA G.; SARDI, JANAINA C. O.; CAMPOS, DEBORA L.; SILVA, ISABEL C.; CAVALCA, LUCIA B.; SCHEFFERS, DIRK-JAN; ROSALEN, PEDRO L.; et al. Antibacterial activity of a new monocarbonyl analog of curcumin MAC 4 is associated with divisome disruption. BIOORGANIC CHEMISTRY, v. 109, APR 2021. (18/00163-0, 14/50880-0, 14/18330-0, 17/50216-0, 15/50162-2, 09/53989-4, 18/15083-2, 14/50926-0, 13/50367-8)

GARCIA, MAYARA A. R.; THEODORO, REINALDO S.; SARDI, JANAINA C. O.; SANTOS, MARIANA B.; AYUSSO, GABRIELA M.; PAVAN, FERNANDO R.; COSTA, ALAN R.; SANTA CRUZ, LUCAS M.; ROSALEN, PEDRO L.; REGASINI, LUIS O.. Design, synthesis and antibacterial activity of chalcones against MSSA and MRSA planktonic cells and biofilms. BIOORGANIC CHEMISTRY, v. 116, NOV 2021. (18/15083-2, 14/50926-0, 09/53989-4, 14/18330-0)

DE ASSIS, LETICIA RIBEIRO; THEODORO, REINALDO DOS SANTOS; SILVA COSTA, MARIA BEATRIZ; SILVA NASCENTES, JULYANNA ANDRADE; DA ROCHA, MIGUEL DIVINO; DE SOUZA BESSA, MELIZA ARANTES; MENEZES, RALCIANE DE PAULA; DILARRI, GUILHERME; HYPOLITO, GIOVANE BOERNER; DOS SANTOS, VANESSA RODRIGUES; et al. Antibacterial Activity of Isobavachalcone (IBC) Is Associated with Membrane Disruption. MEMBRANES, v. 12, n. 3, p. 12-pg., 2022-03-01. (14/18330-0, 18/15083-2)

DOS SANTOS, VANESSA RODRIGUES; CAIAFFA, KARINA SAMPAIO; DE OLIVEIRA, WARLLEY CAMPOS; PEREIRA, JESSE AUGUSTO; ABUNA, GABRIEL FLORES; POLAQUINI, CARLOS ROBERTO; REGASINI, LUIS OCTAVIO; GUIOTTI, AIMEE MARIA; DUQUE, CRISTIANE. Cytotoxicity and effects of curcumin and cinnamaldehyde hybrids on biofilms of oral pathogens. BIOFOULING, JUN 2021. (18/15083-2, 14/18330-0, 17/05892-8)

TEMPONE, ANDRE GUSTAVO; DOS SANTOS THEODORO, REINALDO; ROMANELLI, MAIARA MARIA; FERREIRA, DAYANA AGNES SANTOS; AMARAL, MAIARA; DE ASSIS, LETICIA RIBEIRO; CRUZ, LUCAS MONTEIRO SANTA; COSTA, ALAN ROBERTO; ZANELLA, ROSEMEIRE COBO; CHRISTODOULIDES, MYRON; et al. A new reduced chalcone-derivative affects the membrane permeability and electric potential of multidrug-resistant Enterococcus faecalis. Chemico-Biological Interactions, v. 365, p. 8-pg., 2022-08-10. (14/18330-0, 21/04464-8, 18/26655-7, 19/11979-4, 17/50333-7, 18/15083-2, 09/53989-4)

TORREZAN, GUILHERME SILVA; POLAQUINI, CARLOS ROBERTO; LIMA, MARCELO FREITAS; REGASINI, LUIS OCTAVIO. Use of glycerol, waste glycerol from biodiesel production and other protic solvents in bioactive alpha, beta-unsaturated ketones synthesis. SUSTAINABLE CHEMISTRY AND PHARMACY, v. 16, JUN 2020. (18/15083-2, 09/53989-4, 14/50926-0, 14/18330-0)

DOS SANTOS, MARIANA BASTOS; MARQUES, BEATRIZ CARVALHO; AYUSSO, GABRIELA MIRANDA; ROCHA GARCIA, MAYARA APARECIDA; PARACATU, LUANA CHIQUETTO; PAULI, IVANI; BOLZANI, VANDERLAN SILVA; ANDRICOPULO, ADRIANO DEFINI; XIMENES, VALDECIR FARIAS; ZERAIK, MARIA LUIZA; et al. Chalcones and their B-aryl analogues as myeloperoxidase inhibitors: In silico, in vitro and ex vivo investigations. BIOORGANIC CHEMISTRY, v. 110, MAY 2021. (16/00580-5, 14/18330-0, 09/53989-4, 18/15083-2, 14/50926-0)

LIMA, CAROLINE SPRENGEL; MOTTIN, MELINA; DE ASSIS, LETICIA RIBEIRO; DE MORAES ROSO MESQUITA, NATHALYA CRISTINA; DE PAULA SOUSA, BRUNA KATIELE; COIMBRA, LAIS DURCO; BISPO-DOS-SANTOS, KARINA; ZORN, KIMBERLEY M.; GUIDO, RAFAEL V. C.; EKINS, SEAN; et al. Flavonoids from Pterogyne nitens as Zika virus NS2B-NS3 protease inhibitors. BIOORGANIC CHEMISTRY, v. 109, APR 2021. (16/00194-8, 18/03917-6, 13/07600-3, 14/18330-0, 18/15083-2)

PEREIRA, JESSE AUGUSTO; POLAQUINI, CARLOS ROBERTO; DOS SANTOS, VANESSARODRIGUES; CAIAFFA, KARINA SAMPAIO; RABELO, RAFAELA LARUZO; THEODORO, REINALDO DOS SANTOS; THEODORO, LETICIA HELENA; REGASINI, LUIS OCTAVIO; DUQUE, CRISTIANE. Antibiofilm and cytotoxic effect of 3,3 `-dihydroxycurcumin (DHC) as photosensitizer agent in antimicrobial photodynamic therapy for endodontic purposes. Photodiagnosis and Photodynamic Therapy, v. 36, DEC 2021. (18/15083-2, 14/18330-0, 18/10857-0)

DOS SANTOS, VANESSA RODRIGUES; CAIAFFA, KARINA SAMPAIO; DE OLIVEIRA, WARLLEY CAMPOS; PEREIRA, JESSE AUGUSTO; ABUNA, GABRIEL FLORES; POLAQUINI, CARLOS ROBERTO; REGASINI, LUIS OCTAVIO; GUIOTTI, AIMEE MARIA; DUQUE, CRISTIANE. Cytotoxicity and effects of curcumin and cinnamaldehyde hybrids on biofilms of oral pathogens. BIOFOULING, v. 37, n. 6, p. 591-605, JUL 3 2021. (17/05892-8, 18/15083-2, 14/18330-0)

ANSELMO, DAIANE B.; POLAQUINI, CARLOS R.; MARQUES, BEATRIZ C.; AYUSSO, GABRIELA M.; ASSIS, LETICIA R.; TORREZAN, GUILHERME S.; RAHAL, PAULA; FACHIN, ANA L.; CALMON, MARILIA F.; MARINS, MOZART A.; et al. Curcumin-cinnamaldehyde hybrids as antiproliferative agents against women's cancer cells. MEDICINAL CHEMISTRY RESEARCH, v. 30, n. 11, AUG 2021. (18/15083-2, 14/50880-0, 14/18330-0, 09/53989-4, 14/50926-0)

MARQUES, BEATRIZ C.; SANTOS, MARIANA B.; ANSELMO, DAIANE B.; MONTEIRO, DIEGO A.; GOMES, ELENI; SAIKI, MARILIA F. C.; RAHAL, PAULA; ROSALEN, PEDRO L.; SARDI, JANAINA C. O.; REGASINI, LUIS O.. Methoxychalcones: Effect of Methoxyl Group on the Antifungal Antibacterial and Antiproliferative Activities. Medicinal Chemistry, v. 16, n. 7, p. 881-891, 2020. (14/18330-0, 17/09245-7, 14/18577-5, 09/53989-4, 18/15083-2, 16/08084-7, 14/50926-0)