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Bioorg Med Chem ; 26(5): 1026-1034, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29422332


The TGFß-TGFßR signaling pathway has been reported to play a protective role in the later stages of tumorigenesis via increasing immunosuppressive Treg cells and facilitating the epithelial to mesenchymal transition (EMT). Therefore, inhibition of TGFßR has the potential to enhance antitumor immunity. Herein we disclose the identification and optimization of novel heterobicyclic inhibitors of TGFßRI that demonstrate potent inhibition of SMAD phosphorylation. Application of structure-based drug design to the novel pyrrolotriazine chemotype resulted in improved binding affinity (Ki apparent = 0.14 nM), long residence time (T1/2 > 120 min) and significantly improved potency in the PSMAD cellular assay (IC50 = 24 nM). Several analogs inhibited phosphorylation of SMAD both in vitro and in vivo. Additionally, inhibition of TGFß-stimulated phospho-SMAD was observed in primary human T cells.

Compostos Bicíclicos com Pontes/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Sítios de Ligação , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/farmacologia , Células Cultivadas , Cristalografia por Raios X , Desenho de Drogas , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Simulação de Dinâmica Molecular , Fosforilação , Ligação Proteica , Estrutura Terciária de Proteína , Proteínas Serina-Treonina Quinases/metabolismo , Pirróis/síntese química , Pirróis/química , Pirróis/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Proteínas Smad/metabolismo , Relação Estrutura-Atividade , Linfócitos T/citologia , Linfócitos T/metabolismo , Tiazinas/síntese química , Tiazinas/química , Tiazinas/metabolismo
Bioorg Med Chem Lett ; 22(17): 5550-4, 2012 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-22850211


Benzoyl phenyl urea, a class of insect growth regulator's acts by inhibiting chitin synthesis. Carvacrol, a naturally occurring monoterpenoid is an effective antifungal agent. We have structurally modified carvacrol (2-methyl-5-[1-methylethyl] phenol) by introducing benzoylphenyl urea linkage. Two series of benzoylcarvacryl thiourea (BCTU, 4a-f) and benzoylcarvacryl urea (BCU, 5a-f) derivatives were prepared and characterized by elemental analysis, IR, (1)H and (13)C NMR and Mass spectroscopy. Derivatives 4b, 4d, 4e, 4f and 5d, 5f showed comparable insecticidal activity with the standard BPU lufenuron against Dysdercus koenigii. BCTU derivatives 4c, 4e and BCU 5c showed good antifungal activity against phytopathogenic fungi viz. Magnaporthe grisae, Fusarium oxysporum, Dreschlera oryzae; food spoilage yeasts viz. Debaromyces hansenii, Pichia membranifaciens; and human pathogens viz. Candida albicans and Cryptococcus neoformans. Compounds 5d, 5e and 5f showed potent activity against human pathogens. Moderate and selective activity was observed for other compounds. All the synthesized compounds were non-haemolytic. These compounds have potential application in agriculture and medicine.

Antifúngicos/química , Antifúngicos/farmacologia , Monoterpenos/química , Monoterpenos/farmacologia , Compostos de Fenilureia/química , Compostos de Fenilureia/farmacologia , Animais , Fungos/efeitos dos fármacos , Humanos , Insetos/efeitos dos fármacos , Inseticidas/química , Inseticidas/farmacologia , Testes de Sensibilidade Microbiana , Micoses/tratamento farmacológico , Tioureia/química , Tioureia/farmacologia
Acta Crystallogr Sect E Struct Rep Online ; 67(Pt 7): o1605, 2011 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-21837013


In the title racemic compound, C(26)H(32)N(2)O(3), an intra-molecular O-H⋯N hydrogen bond is formed between the phenolic OH group and the tertiary amine N atom. Another O-H⋯N hydrogen bond that is formed between the OH group and the pyridine N atom links the mol-ecules into a polymeric chain extending along the a axis. The structure is further stabilized by intramolecular and intermolecular C-H⋯O interactions.

J Org Chem ; 76(6): 1742-50, 2011 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-21314094


Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants as well as well-known carcinogens. Therefore, it is important to develop an effective receptor for the detection and quantification of such molecules in solution. In view of this, a 1,3-dinaphthalimide derivative of calix[4]arene (L) has been synthesized and characterized, and the structure has been established by single crystal XRD. In the crystal lattice, intermolecular arm-to-arm π···π overlap dominates and thus L becomes a promising receptor for providing interactions with the aromatic species in solution, which can be monitored by following the changes that occur in its fluorescence and absorption spectra. On the basis of the solution studies carried out with about 17 derivatives of the aromatic guest molecular systems, it may be concluded that the changes that occur in the fluorescence intensity seem to be proportional to the number of aromatic rings present and thus proportional to the extent of π···π interaction present between the naphthalimide moieties and the aromatic portion of the guest molecule. Though the nonaromatic portion of the guest species affects the fluorescence quenching, the trend is still based on the number of rings present in these. Four guest aldehydes are bound to L with K(ass) of 2000-6000 M(-1) and their minimum detection limit is in the range of 8-35 µM. The crystal structure of a naphthaldehyde complex, L.2b, exhibits intermolecular arm-to-arm as well as arm-to-naphthaldehyde π···π interactions. Molecular dynamics studies of L carried out in the presence of aromatic aldehydes under vacuum as well as in acetonitrile resulted in exhibiting interactions observed in the solid state and hence the changes observed in the fluorescence and absorption spectra are attributable for such interactions. Complex formation has also been delineated through ESI MS studies. Thus L is a promising receptor that can recognize PAHs by providing spectral changes proportional to the aromatic conjugation of the guest and the extent of aromatic π···π interactions present between L and the guest.

Chem Commun (Camb) ; 46(24): 4345-7, 2010 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-20461281


A fluorescence turn-on receptor based on triazole linked calix[4]arene (L) for selective recognition of Zn(2+) in aqueous-methanolic HEPES buffer has been developed and showed its utility for sensing Zn(2+) in blood serum milieu.

Calixarenos/química , Triazóis/química , Zinco/sangue , Técnicas Biossensoriais , Cristalografia por Raios X , Conformação Molecular , Espectrometria de Fluorescência
Acta Crystallogr Sect E Struct Rep Online ; 66(Pt 7): o1614, 2010 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-21587846


In the title Mannich base, C(20)H(21)N(3)O(3), an isatin derivative of thymol, the O-CH(2)-C(=O)-N(H)-N fragment connect-ing the aromatic and fused-ring systems is approximately planar, with the N-N single bond in a Z configuration. The amino H atom of this N-N fragment is intra-molecularly hydrogen bonded to the carbonyl O atom of the indolinone fused ring as well as to the phen-oxy O atom of the aromatic ring. The amino H atom of the indoline fused ring forms a hydrogen bond with the double-bond O atom of an adjacent mol-ecule, this hydrogen bond giving rise to a linear chain motif.