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1.
Clin Exp Pharmacol Physiol ; 47(1): 143-157, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31563143

RESUMO

Cytochrome P450 1B1, considered as one of the novel chemotherapeutic targets involved in cancer prevention and therapy is also associated with the conversion of procarcinogens into their active metabolites. The aryl hydrocarbon receptor (AhR) is responsible for mediating different biological responses to a wide variety of environmental pollutants and also causes transcriptional activation of cytochrome P450 enzymes including CYP1B1 and thus plays a pivotal role for initiating cancer and its progression. On the other hand, active carcinogenic metabolites and reactive oxygen species-mediated stress alter different molecular signalling pathways and gene expressions. Quinazoline derivatives are recognized for their diversified biological activities including anticancer properties. The current study was designed for evaluation of chemotherapeutic efficacy of a synthetic quinazolinone derivative BNUA-3 against hepatocellular cancer in Sprague-Dawley (SD) rats. A detailed in vivo analysis was performed by administrating BNUA-3 (15, 30 mg/kg b.w. for 28 days, i.p.) in N-Nitrosodiethylamine + 2-Acetylaminofluorene induced partially hepatectomized liver cancer in SD rats. This was followed by morphological evaluations, biochemical estimations and analysis of different mRNA and protein expressions. The results demonstrated the potency of BNUA-3 in efficient restoration of the altered morphology of liver, its protective effect against lipid peroxidation, enzymic and non-enzymic antioxidants levels in liver tissue which was disrupted after cancer induction. The study also demonstrated downregulation of AhR, CYP1B1 and Keap1 expressions with subsequent augmentation of protective Nrf2, HO-1, NQO1 and GSTA1 expressions thus, revealing the chemotherapeutic potency of BNUA-3 in inhibiting liver carcinogenesis through AhR/CYP1B1/Nrf2/Keap1 pathway.

2.
PLoS Biol ; 17(6): e3000281, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31185007

RESUMO

Rhino- and enteroviruses are important human pathogens, against which no antivirals are available. The best-studied inhibitors are "capsid binders" that fit in a hydrophobic pocket of the viral capsid. Employing a new class of entero-/rhinovirus inhibitors and by means of cryo-electron microscopy (EM), followed by resistance selection and reverse genetics, we discovered a hitherto unknown druggable pocket that is formed by viral proteins VP1 and VP3 and that is conserved across entero-/rhinovirus species. We propose that these inhibitors stabilize a key region of the virion, thereby preventing the conformational expansion needed for viral RNA release. A medicinal chemistry effort resulted in the identification of analogues targeting this pocket with broad-spectrum activity against Coxsackieviruses B (CVBs) and compounds with activity against enteroviruses (EV) of groups C and D, and even rhinoviruses (RV). Our findings provide novel insights in the biology of the entry of entero-/rhinoviruses and open new avenues for the design of broad-spectrum antivirals against these pathogens.

4.
Mini Rev Med Chem ; 19(19): 1564-1576, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30827237

RESUMO

Iron overload disorder and diseases where iron mismanagement plays a crucial role require orally available iron chelators with favourable pharmacokinetic and toxicity profile. Desferrithiocin (DFT), a tridentate and orally available iron chelator has a favourable pharmacokinetic profile but its use has been clinically restricted due to its nephrotoxic potential. The chemical architecture of the DFT has been naturally well optimized for better iron chelation and iron clearance from human biological system. Equally they are also responsible for its toxicity. Hence, subsequent research has been devoted to develop a non-nephrotoxic analogue of DFT without losing its iron clearance ability. The review has been designed to classify the compounds reported till date and to discuss the structure activity relationship with reference to modifications attempted at different positions over pyridine and thiazoline ring of DFT. Compounds are clustered under two major classes: (i) Pyridine analogues and (ii) phenyl analogue and further each class has been further subdivided based on the presence or absence and the number of hydroxy functional groups present over pyridine or phenyl ring of the DFT analogues. Finally a summary and few insights into the development of newer analogues are provided.


Assuntos
Di-Hidropiridinas/química , Quelantes de Ferro/química , Tiazóis/química , Derivados de Benzeno/química , Di-Hidropiridinas/uso terapêutico , Humanos , Quelantes de Ferro/uso terapêutico , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/patologia , Piridinas/química , Relação Estrutura-Atividade , Tiazóis/uso terapêutico
5.
Eur J Pharm Sci ; 131: 177-194, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30776468

RESUMO

Microsomal cytochrome P450 (CYP) enzymes, isolated from recombinant bacterial/insect/yeast cells, are extensively used for drug metabolism studies. However, they may not always portray how a developmental drug would behave in human cells with intact intracellular transport mechanisms. This study emphasizes the usefulness of human HEK293 kidney cells, grown in 'suspension' for expression of CYPs, in finding potent CYP1A1/CYP1B1 inhibitors, as possible anticancer agents. With live cell-based assays, quinazolinones 9i/9b were found to be selective CYP1A1/CYP1B1 inhibitors with IC50 values of 30/21 nM, and > 150-fold selectivity over CYP2/3 enzymes, whereas they were far less active using commercially-available CYP1A1/CYP1B1 microsomal enzymes (IC50, >10/1.3-1.7 µM). Compound 9i prevented CYP1A1-mediated benzo[a]pyrene-toxicity in normal fibroblasts whereas 9b completely reversed cisplatin resistance in PC-3/prostate, COR-L23/lung, MIAPaCa-2/pancreatic and LS174T/colon cancer cells, underlining the human-cell-assays' potential. Our results indicate that the most potent CYP1A1/CYP1B1 inhibitors would not have been identified if one had relied merely on microsomal enzymes.


Assuntos
Citocromo P-450 CYP1A1 , Citocromo P-450 CYP1B1 , Inibidores das Enzimas do Citocromo P-450/química , Inibidores das Enzimas do Citocromo P-450/farmacologia , Quinazolinonas , Antineoplásicos/farmacologia , Benzo(a)pireno/toxicidade , Bioensaio , Linhagem Celular , Cisplatino/farmacologia , Citocromo P-450 CYP1A1/antagonistas & inibidores , Citocromo P-450 CYP1A1/química , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1B1/antagonistas & inibidores , Citocromo P-450 CYP1B1/química , Citocromo P-450 CYP1B1/genética , Citocromo P-450 CYP1B1/metabolismo , Resistencia a Medicamentos Antineoplásicos , Humanos , Microssomos Hepáticos/enzimologia , Modelos Moleculares , Quinazolinonas/química , Quinazolinonas/farmacologia
6.
Eur J Med Chem ; 165: 115-132, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30665142

RESUMO

Inhibition of cyclin dependent kinase 4 (Cdk4) prevents cancer cells from entering the early G0/G1 phase of the cell division cycle whereas inhibiting tubulin polymerization blocks cancer cells' ability to undergo mitosis (M) late in the cell cycle. We had reported earlier that two non-planar and relatively non-toxic fascaplysin derivatives, an indole and a tryptoline, inhibit Cdk4 with IC50 values of 6.2 and 10 µM, respectively. Serendipitously, we had also found that they inhibited tubulin polymerization. The molecules were efficacious in mouse tumor models. We have now identified Cink4T in a 59-compound quinazolinone library, designed on the basis of ligand-based virtual screening, as a compound that inhibits Cdk4 and tubulin. Its IC50 value for Cdk4 inhibition is 0.47 µM and >50 µM for inhibition of Cdk1, Cdk2, Cdk6, Cdk9. Cink4T inhibits tubulin polymerization with an IC50 of 0.6 µM. Molecular modelling studies on Cink4T with Cdk4 and tubulin crystal structures lend support to these observations. Cancer cell cycle analyses confirm that Cink4T blocks cells at both G0/G1 and M phases as it should if it were to inhibit both Cdk4 and tubulin polymerization. Our results show, for the very first time, that virtual screening can be used to design novel inhibitors that can potently block two crucial phases of the cell division cycle.


Assuntos
Antineoplásicos/química , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinazolinonas/farmacologia , Tubulina (Proteína)/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Ensaios de Triagem em Larga Escala , Humanos , Camundongos , Polimerização/efeitos dos fármacos , Quinazolinonas/química , Bibliotecas de Moléculas Pequenas , Tubulina (Proteína)/metabolismo
7.
Eur J Med Chem ; 163: 28-36, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30503941

RESUMO

Phytoestrogens are class of natural compounds that shares structural similarity with estrogen and has the capacity to alter the fertilization in mammals. Till early 1990s, the natural phytoestrogens as well as their synthetic analogues were explored for their fertility modulating activity. During late 1990s, two findings renewed the interest on phytoestrogens as means to control hormone induced cancer: (i) revelation of overexpression of CYP1B1 in breast & ovarian cancer and (ii) protection offered by alphanapthoflavone (ANF) against hormone induced cancer. The objective of the review is to summarize the CYP1B1 inhibitory activity of phytoestrogens and their synthetic analogues reported till date. This review is an attempt to classify phytoestrogens and their synthetic analogues on their chemical architecture rather than simply by their chemical class (flavones, stilbenes etc.). This provides a broader sense to cluster many chemical classes under a particular chemical architecture/framework. Accordingly, we divided the phytoestrogen into three different classes based on two aryl groups (Ar) separated by linker (X), which may be either cyclic (c) or linear (l). The number in subscript to X denotes number of atoms: (i) Ar-cX4-Ar, (ii) Ar-lX3-Ar and (iii) Ar-lX2-Ar. This provides an opportunity to cluster flavones, quinolines and quinazolinones under Ar-cX4-Ar class, while biphenyl ureas and chalcones under Ar-lX3-Ar class. We believe in coming years many chemical scaffolds may be clustered under this framework.


Assuntos
Antineoplásicos Fitogênicos/química , Citocromo P-450 CYP1B1/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Fitoestrógenos/química , Animais , Antineoplásicos Fitogênicos/classificação , Classificação , Análise por Conglomerados , Inibidores Enzimáticos/química , Inibidores Enzimáticos/classificação , Humanos , Mimetismo Molecular , Neoplasias/induzido quimicamente
8.
Medchemcomm ; 9(7): 1164-1171, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30109004

RESUMO

A series of 2-methoxy-4-(5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)phenol (pyrazoline) derivatives (2-6) have been synthesized and tested for human monoamine oxidase (hMAO) inhibitory activity. The most active derivative (2) behaved as a competitive hMAO-A inhibitor, with an inhibition constant value of 0.08 µM and a strong hMAO-A selectivity (Ki(hMAO-B)/Ki(hMAO-A) > 1751). In addition, 2 exhibited little to no cytotoxic effects up to a 25 µM concentration and provided the best blood-brain barrier permeability among the derivatives synthesized. Molecular dynamics simulations revealed that a chlorine substituent at the para-position of the phenyl ring in 2 enabled a π-π stacking interaction with Tyr407 and Tyr444 that resulted in the formation of an "aromatic sandwich" structure. Consequently, this tight-binding aromatic cage culminated in a dramatically reduced active site volume that is believed to be the origin of the observed selectivity between the hMAO-A and hMAO-B isozymes. Removal of the chlorine from 2 disrupted the favorable intermolecular interactions and resulted in a selectivity change towards hMAO-B.

9.
Mini Rev Med Chem ; 18(19): 1611-1623, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30068272

RESUMO

Farnesyl Transferase is a hetero-dimer transferase that targets Ras proteins and attaches a farnesyl group to it. This Ras protein, on localization to the cell membrane, has the ability to induce activation of various growth and proliferation pathways of the cell. Over-activation of mutated Ras may lead to the development of cancer. Farnesyl Transferase catalyses the initial step in the posttranslational modification of normal as well as mutated Ras gene, thus facilitating its tethering to the cell membrane. Inhibition of Farnesyl Transferase is the main step in restricting the activity of mutant Ras protein. Thus the above enzyme has emerged as a novel target for anti-cancer agents. Here we review the role of Farnesyl Transferase in tumorigenesis and various compounds of synthetic and natural origin acting as Farnesyl Transferase inhibitors as potential anti-cancer agents.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Farnesiltranstransferase/antagonistas & inibidores , Animais , Antineoplásicos/química , Inibidores Enzimáticos/química , Farnesiltranstransferase/química , Farnesiltranstransferase/metabolismo , Genes ras , Humanos , Sistema de Sinalização das MAP Quinases , Neoplasias/enzimologia , Neoplasias/metabolismo , Conformação Proteica , Processamento de Proteína Pós-Traducional , Relação Estrutura-Atividade
10.
Acta Crystallogr E Crystallogr Commun ; 74(Pt 5): 718-723, 2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29850099

RESUMO

In the title compounds, C11H12N6OS (I) and C10H11N7OS (II), the di-amino-pyrimidine ring makes dihedral angles of 71.10 (9)° with the pyridine ring in (I) and 62.93 (15)° with the pyrazine ring in (II). The ethanamine group, -CH2-C(=O)-NH- lies in the plane of the pyridine and pyrazine rings in compounds (I) and (II), respectively. In both compounds, there is an intra-molecular N-H⋯N hydrogen bond forming an S(7) ring motif and a short C-H⋯O inter-action forming an S(6) loop. In the crystals of both compounds, mol-ecules are linked by pairs of N-H⋯N hydrogen bonds, forming inversion dimers with R22(8) ring motifs. In (I), the dimers are linked by N-H⋯O and N-H⋯N hydrogen bonds, forming layers parallel to (1[Formula: see text] [Formula: see text]). The layers are linked by offset π-π inter-actions [inter-centroid distance = 3.777 (1) Å], forming a three-dimensional supra-molecular structure. In (II), the dimers are linked by N-H⋯O, N-H⋯N and C-H⋯O hydrogen bonds, also forming a three-dimensional supra-molecular structure.

11.
Sci Rep ; 7(1): 14453, 2017 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-29089569

RESUMO

Peroxisome proliferator-activated receptor γ (PPARγ) has received significant attention as a key regulator of glucose and lipid homeostasis. In this study, we synthesized and tested a library of novel 5-benzylidene-thiazolidin-2,4-dione (BTZD) derivatives bearing a substituent on nitrogen of TZD nucleus (compounds 1a-1k, 2i-10i, 3a, 6a, and 8a-10a). Three compounds (1a, 1i, and 3a) exhibited selectivity towards PPARγ and were found to be weak to moderate partial agonists. Surface Plasmon Resonance (SPR) results demonstrated binding affinity of 1a, 1i and 3a towards PPARγ. Furthermore, docking experiments revealed that BTZDs interact with PPARγ through a distinct binding mode, forming primarily hydrophobic contacts with the ligand-binding pocket (LBD) without direct H-bonding interactions to key residues in H12 that are characteristic of full agonists. In addition, 1a, 1i and 3a significantly improved hyperglycemia and hyperlipidaemia in streptozotocin-nicotinamide (STZ-NA)-induced diabetic rats at a dose of 36 mg/kg/day administered orally for 15 days. Histopathological investigations revealed that microscopic architecture of pancreatic and hepatic cells improved in BTZDs-treated diabetic rats. These findings suggested that 1a, 1i and 3a are very promising pharmacological agents by selectively targeting PPARγ for further development in the clinical treatment of type 2 diabetes mellitus.


Assuntos
Compostos de Benzilideno/farmacologia , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Modelos Animais de Doenças , Glucose/metabolismo , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/farmacologia , Masculino , Modelos Moleculares , Simulação de Acoplamento Molecular , PPAR gama/agonistas , Conformação Proteica , Ratos , Ratos Wistar , Tiazolidinedionas/farmacologia
12.
Acta Crystallogr E Crystallogr Commun ; 73(Pt 7): 996-1000, 2017 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-28775869

RESUMO

In the title compounds, C14H17N5OS (I) and C13H15N5O2S (II), the dihedral angle between the pyrimidine and benzene rings is 58.64 (8)° in (I) and 78.33 (9)° in (II). In both compounds, there is an intra-molecular C-H⋯O hydrogen bond, and in (II) there is also an intra-molecular N-H⋯N hydrogen bond present. In the crystals of both compounds, a pair of N-H⋯N hydrogen bonds links the individual mol-ecules to form inversion dimers with R22(8) ring motifs. In (I), the dimers are linked by N-H⋯O and C-H⋯O hydrogen bonds, enclosing R21(14), R21(11) and R21(7) ring motifs, forming layers parallel to the (100) plane. There is also an N-H⋯π inter-action present within the layer. In (II), the inversion dimers are linked by N-H⋯O hydrogen bonds enclosing an R44(18) ring motif. The presence of N-H⋯O and C-H⋯O hydrogen bonds generate an R21(6) ring motif. The combination of these various hydrogen bonds results in the formation of layers parallel to the (1-11) plane.

13.
Food Chem Toxicol ; 108(Pt A): 53-62, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28716444

RESUMO

Cellular growth inhibition exerted by thiosemicarbazones is mainly attributed to down-regulation of ribonucleotide reductase (RNR) activity, with RNR being responsible for the rate-limiting step of de novo DNA synthesis. In this study, we investigated the antineoplastic effects of three newly synthesized thiosemicarbazone derivatives, thiazolyl hydrazones, in human HL-60 promyelocytic leukemia cells. The cytotoxicity of compounds alone and in combination with arabinofuranosylcytosine (AraC) was determined by growth inhibition assays. Effects on deoxyribonucleoside triphosphate (dNTP) concentrations were quantified by HPLC, and the incorporation of radio-labeled 14C-cytidine into nascent DNA was measured using a beta counter. Cell cycle distribution was analyzed by FACS, and protein levels of RNR subunits and checkpoint kinases were evaluated by Western blotting. VG12, VG19, and VG22 dose-dependently decreased intracellular dNTP concentrations, impaired cell cycle progression and, consequently, inhibited the growth of HL-60 cells. VG19 also lowered the protein levels of RNR subunits R1 and R2 and significantly diminished the incorporation of radio-labeled 14C-cytidine, being equivalent to an inhibition of DNA synthesis. Combination of thiazolyl hydrazones with AraC synergistically potentiated the antiproliferative effects seen with each drug alone and might therefore improve conventional chemotherapeutic regimens for the treatment of human malignancies such as acute promyelocytic or chronic myelogenous leukemia.


Assuntos
Citarabina/farmacocinética , Regulação para Baixo/efeitos dos fármacos , Hidrazonas/farmacocinética , Ribonucleotídeo Redutases/antagonistas & inibidores , Tiossemicarbazonas/farmacocinética , Ciclo Celular/efeitos dos fármacos , Citarabina/administração & dosagem , Citarabina/farmacologia , Sinergismo Farmacológico , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Células HL-60 , Humanos , Hidrazonas/administração & dosagem , Hidrazonas/química , Hidrazonas/farmacologia , Estrutura Molecular , Ribonucleotídeo Redutases/genética , Ribonucleotídeo Redutases/metabolismo , Tiossemicarbazonas/administração & dosagem , Tiossemicarbazonas/química , Tiossemicarbazonas/farmacologia
14.
Acta Crystallogr E Crystallogr Commun ; 73(Pt 4): 467-471, 2017 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-28435699

RESUMO

The title compounds, C12H12ClN5OS, (I), and C12H12ClN5OS, (II), are 2-[(di-amino-pyrimidin-2-yl)sulfan-yl]acetamides. Compound (II), crystallizes with two independent mol-ecules (A and B) in the asymmetric unit. In each of the mol-ecules, in both (I) and (II), an intra-molecular N-H⋯N hydrogen bond forms an S(7) ring motif. The pyrimidine ring is inclined to the benzene ring by 42.25 (14)° in (I), and by 59.70 (16) and 62.18 (15)° in mol-ecules A and B, respectively, of compound (II). In the crystal of (I), mol-ecules are linked by pairs of N-H⋯N hydrogen bonds, forming inversion dimers with an R22(8) ring motif. The dimers are linked via bifurcated N-H⋯O and C-H⋯O hydrogen bonds, forming corrugated layers parallel to the ac plane. In the crystal of (II), the A mol-ecules are linked through N-H⋯O and N-H⋯Cl hydrogen bonds, forming layers parallel to (100). The B mol-ecules are also linked by N-H⋯O and N-H⋯Cl hydrogen bonds, also forming layers parallel to (100). The parallel layers of A and B mol-ecules are linked via N-H⋯N hydrogen bonds, forming a three-dimensional structure.

15.
Eur J Med Chem ; 130: 320-327, 2017 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-28259840

RESUMO

CYP1B1 is implicated to have a role in the development of breast, ovarian, renal, skin and lung carcinomas. It has been suggested that identification of potent and specific CYP1B1 inhibitors can lead to a novel treatment of cancer. Flavonoids have a compact rigid skeleton which fit precisely within the binding cavity of CYP1B1. Systematic isosteric replacement of flavonoid 'O' atom with 'N' atom led to the prediction that a 'quinazoline' scaffold could be the basis for designing potential CYP1B1 inhibitors. A total of 20 quinazoline analogs were synthesized and screened for CYP1B1 and CYP1A1 inhibition in Sacchrosomes™. IC50 determinations of six compounds with capability of inhibiting CYP1B1 identified quinazolines 5c and 5h as the best candidates for CYP1B1 inhibition, with IC50 values in the nM range. Further selectivity studies with homologous CYPs, belonging to the CYP1, CYP2 and CYP3 family of enzymes, showed that the compounds are likely to be free from critical drug-drug interaction liability. Molecular modelling studies were performed to rationalize the observed enzymatic inhibitions. Further biological studies in live yeast and human cells, harboring CYP1A1 and CYP1B1 enzymes, have illustrated the most potent compounds' cellular permeability and capability of potently inhibiting CYP1B1 enzyme expressed within live cells.


Assuntos
Antineoplásicos/química , Citocromo P-450 CYP1B1/antagonistas & inibidores , Quinazolinas/farmacologia , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Permeabilidade da Membrana Celular , Células Cultivadas , Citocromo P-450 CYP1A1 , Família 2 do Citocromo P450/efeitos dos fármacos , Família 3 do Citocromo P450/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Humanos , Modelos Moleculares , Quinazolinas/química , Quinazolinas/farmacocinética , Leveduras/citologia
16.
Curr Comput Aided Drug Des ; 13(4): 346-361, 2017 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-28294048

RESUMO

BACKGROUND: Chikungunya is a viral infection caused by Chikungunya virus (CHIKV), an arbovirus transmitted through mosquito (Aedes aegypti and Aedes albopictus) bite. The virus from sylvatic cycle in Africa mutated to new vector adaptation and became one of the major emerging and re-emerging viral infections in the past decade, affecting more than 40 countries. Efforts are being made by many researches to develop means to prevent and control the infection through vaccines and vector control strategy. On the other hand, search for novel chemotherapeutic agents for the treatment of infected patients is on. Approach of repurposed drug is one way of identifying an existing drug for the treatment of CHIKV infection. OBJECTIVE: Review the history of CHIKV nsp2 protease inhibitors derived through structure-based computer-aided drug design along with phytochemicals identified as anti-CHIKV agents. METHODS: A survey on CHIKV inhibitors reported till date has been carriedout. The data obtained were organized and discussed under natural substances and synthetic derivatives obtained as result of rational design. RESULTS: The review provides a well organized content in chronological order that has highly significant information for medicinal chemist who wish to explore the area of Anti-CHIKV drug design and development. Natural compounds with different scaffolds provides an opportunity to explore Ligand based drug design (LBDD), while rational drug design approaches provides opportunity to explore the Structure based drug design. CONCLUSION: From the presented mini-review, readers can understand that this area is less explored and has lots of potential in anti-CHIKVviral drug design & development. of reported literature inferred that, unlike other viral proteases, the nsP2 protease can be targeted for CHIKV viral inhibition. The HTVS process for the identification of anti-CHIK agents provided a few successive validated lead compounds against CHIKV infections.


Assuntos
Antivirais/química , Antivirais/farmacologia , Febre de Chikungunya/tratamento farmacológico , Vírus Chikungunya/efeitos dos fármacos , Projeto Auxiliado por Computador , Desenho de Drogas , Descoberta de Drogas/métodos , Animais , Febre de Chikungunya/enzimologia , Febre de Chikungunya/transmissão , Vírus Chikungunya/fisiologia , Cisteína Endopeptidases/metabolismo , Ensaios de Triagem em Larga Escala/métodos , Humanos , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
17.
Acta Crystallogr E Crystallogr Commun ; 73(Pt 2): 306-309, 2017 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-28217364

RESUMO

The title compounds, C16H15N5OS, (I), and C12H12FN5OS, (II), are [(di-amino-pyrimidine)-sulfan-yl]acetamide derivatives. In (I), the pyrimidine ring is inclined to the naphthalene ring system by 55.5 (1)°, while in (II), the pyrimidine ring is inclined to the benzene ring by 58.93 (8)°. In (II), there is an intra-molecular N-H⋯N hydrogen bond and a short C-H⋯O contact. In the crystals of (I) and (II), mol-ecules are linked by pairs of N-H⋯N hydrogen bonds, forming inversion dimers with R22(8) ring motifs. In the crystal of (I), the dimers are linked by bifurcated N-H⋯(O,O) and C-H⋯O hydrogen bonds, forming layers parallel to (100). In the crystal of (II), the dimers are linked by N-H⋯O hydrogen bonds, also forming layers parallel to (100). The layers are linked by C-H⋯F hydrogen bonds, forming a three-dimensional architecture.

18.
Eur J Med Chem ; 126: 879-893, 2017 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-27988463

RESUMO

Thiazolidinediones a class of drug, that provided a major breakthrough in the management of type 2 diabetes since 1990. Following the discovery of PPARs, TZDs were the first class to be reported as PPARγ modulators. This review is an attempt to summarize the chemical modifications around TZDs in past two decades to obtain a potent antidiabetic molecule. TZDs literature were initially dominated by their hypoglycemic & hypolipidemic activities, later PPARγ activity was also been incorporated. Moreover, in some cases, both benzyl and benzylidene derivatives were reported in the same manuscript for the sake of comparison. We thought of presenting the review on the basis of the variation in the linker region. Optimal linker at the time of discovery of the Ciglitazone was oxymethyl and it went on to evolve as oxyethyl (Pioglitazone) and oxyethylamino (Rosiglitazone). Few attempts were made to restrict the flexibility of the linker by introducing the cyclic structures and were summarized immediately after the respective linker class.


Assuntos
Hipoglicemiantes/farmacologia , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Tiazolidinedionas/farmacologia , Animais , Humanos , Hipoglicemiantes/química , Tiazolidinedionas/química
19.
Org Biomol Chem ; 14(38): 8931-8936, 2016 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-27714268

RESUMO

Highly selective CYP1B1 inhibitors have potential in the treatment of hormone-induced breast and prostate cancers. Mimicry of potent and selective CYP1B1 inhibitors, α-naphthoflavone and stilbenes, revealed that two sets of hydrophobic clusters suitably linked via a polar linker could be implanted into a new scaffold 'biphenyl ureas' to create potentially a new class of CYP1B1 inhibitors. A series of sixteen biphenyl ureas were synthesized and screened for CYP1B1 and CYP1A1 inhibition in Sacchrosomes™, yeast-derived recombinant microsomal enzymes. The most active human CYP1B1 inhibitors were further studied for their selectivity against human CYP1A1, CYP1A2, CYP3A4 and CYP2D6 enzymes. The meta-chloro-substituted biphenyl urea 5h was the most potent inhibitor of CYP1B1 with IC50 value of 5 nM. It displayed excellent selectivity over CYP1A1, CYP1A2, CYP3A4 and CYP2D6 (IC50 >10 µM in the four CYP assays, indicating >2000-fold selectivity). Similarly, two methoxy-substituted biphenyl ureas 5d and 5e also displayed potent and selective inhibition of CYP1B1 with IC50 values of 69 and 58 nM, respectively, showing >62 and >98-fold selectivity over CYP1A1, CYP1A2, CYP3A4 and CYP2D6 enzymes. In order to probe if the relatively insoluble biphenyl ureas were cell permeable and if they could at all be used for future cellular studies, their CYP1B1 inhibition was investigated in live recombinant human and yeast cells. Compound 5d displayed the most potent inhibition with IC50s of 20 nM and 235 nM, respectively, in the two cell-based assays. The most potent and selective CYP1B1 inhibitor (compound 5h) from Sacchrosomes, also displayed potent inhibition in live cell assays. Molecular modeling was performed to understand the trends in potency and selectivity observed in the panel of five CYP isoenzymes used for the in vitro studies.


Assuntos
Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Citocromo P-450 CYP1B1/antagonistas & inibidores , Ureia/análogos & derivados , Ureia/farmacologia , Citocromo P-450 CYP1B1/metabolismo , Células HEK293 , Halogenação , Humanos , Modelos Moleculares , Saccharomyces cerevisiae/efeitos dos fármacos , Proteínas de Saccharomyces cerevisiae/antagonistas & inibidores , Proteínas de Saccharomyces cerevisiae/metabolismo
20.
Acta Crystallogr E Crystallogr Commun ; 72(Pt 8): 1171-5, 2016 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-27536406

RESUMO

The title compounds, C12H12N6O3S·H2O, (I), and C12H12ClN5OS, (II), are 2-[(4,6-di-amino-pyrimidin-2-yl)sulfan-yl]acetamides. Compound (I) crystallized as a monohydrate. In both compounds, the mol-ecules have a folded conformation, with the pyrimidine ring being inclined to the benzene ring by 56.18 (6)° in (I) and by 67.84 (6)° in (II). In both mol-ecules, there is an intra-molecular N-H⋯N hydrogen bond stabilizing the folded conformation. In (I), there is also a C-H⋯O intra-molecular short contact, and in (II) an intra-molecular N-H⋯Cl hydrogen bond is present. In the crystal of (I), mol-ecules are linked by a series of N-H⋯O, O-H⋯O and O-H⋯N hydrogen bonds, forming undulating sheets parallel to the (100). The sheets are linked via an N-H⋯Owater hydrogen bond, forming a three-dimensional network. In the crystal of (II), mol-ecules are linked by a series of N-H⋯O, N-H⋯N and C-H⋯O hydrogen bonds, forming slabs parallel to (001).

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