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1.
J Comput Aided Mol Des ; 38(1): 16, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38556596

RESUMO

The kinesin spindle protein (Eg5) is a mitotic protein that plays an essential role in the formation of the bipolar spindles during the mitotic phase. Eg5 protein controls the segregation of the chromosomes in mitosis which renders it a vital target for cancer treatment. In this study our approach to identifying novel scaffold for Eg5 inhibitors is based on targeting the novel allosteric pocket (α4/α6/L11). Extensive computational techniques were applied using ligand-based virtual screening and molecular docking by two approaches, MOE and AutoDock, to screen a library of commercial compounds. We identified compound 8-(3-(1H-imidazol-1-ylpropylamino)-3-methyl-7-((naphthalen-3-yl)methyl)-1H-purine-2, 6 (3H,7H)-dione (compound 5) as a novel scaffold for Eg5 inhibitors. This compound inhibited cancer cell Eg5 ATPase at 2.37 ± 0.15 µM. The molecular dynamics simulations revealed that the identified compound formed stable interactions in the allosteric pocket (α4/α6/L11) of the receptor, indicating its potential as a novel Eg5 inhibitor.


Assuntos
Cinesinas , Simulação de Dinâmica Molecular , Simulação de Acoplamento Molecular , Cinesinas/metabolismo , Ligantes , Mitose
2.
J Biomol Struct Dyn ; : 1-14, 2023 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-38084778

RESUMO

The COVID-19 pandemic was caused by the SARS-CoV-2 virus, frequent mutations occurred to the wild-type virus resulting in evolved new variants. The WHO classified the new variants as 'Variants of Concern'. SARS-CoV-2 omicron evolved as the dominating variant at the end of 2021. Dolutegravir and etravirine were identified as inhibitors of SARS-CoV-2 entry to host cells in Omicron variants. In this study, combined in silico methods such as molecular docking, molecular dynamics, Principal component analysis, binding-free energy calculations, and Per Residues calculations were applied to investigate the mechanism of the bindings of the two inhibitors. The molecular dynamics results revealed the stability of dolutegravir-spike and etravirine-spike complexes in a similar manner to apo-protein. Dolutegravir and etravirine formed H-bonds and salt bridges with Omicron spike protein. The 2,4-difluoro phenyl moiety of dolutegravir plays an important role in binding the ligand. The binding mode and interactions of the two compounds indicated that Arg403, Tyr449, Tyr453, Arg493, Ser496, Arg498, Thr500, Tyr501, Gln502 and His505 are the key residues. The Principal Component Analyses suggested that no significant conformational changes happened for the two complexes during the simulations. Binding-free energy calculations showed that van der Waals interactions were the most important interactions for ligands' binding. Per-residue free energy decomposition revealed residues Arg493, Arg498, and Tyr501 contributed to the binding of the ligands through H-bonds and salt bridges formation while His505 contributed to H-bonds and Pi-Pi stacking and Phe497 contributed to hydrophobic interactions between ligands and Omicron spike protein.Communicated by Ramaswamy H. Sarma.

3.
Eur J Med Chem ; 260: 115766, 2023 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-37678141

RESUMO

A series of novel benzofuran-based compounds 7a-s were designed, synthesized, and investigated in vitro as acetylcholinesterase inhibitors (AChEIs). Compounds 7c and 7e displayed promising inhibitory activity with IC50 values of 0.058 and 0.086 µM in comparison to donepezil with an IC50 value of 0.049 µM. The new molecules' antioxidant evaluation revealed that 7c, 7e, 7j, 7n, and 7q produced the strongest DPPH scavenging activity when compared to vitamin C. As it was the most promising AChEI, compound 7c was selected for further biological evaluation. Acute and chronic toxicity studies exhibited that 7c showed no signs of toxicity or adverse events, no significant differences in the blood profile, and an insignificant difference in hepatic enzymes, glucose, urea, creatinine, and albumin levels in the experimental rat group. Furthermore, 7c did not produce histopathological damage to normal liver, kidney, heart, and brain tissues, ameliorated tissue malonaldehyde (MDA) and glutathione (GSH) levels and reduced the expression levels of the APP and Tau genes in AD rats. Molecular docking results of compounds 7c and 7e showed good binding modes in the active site of the acetylcholinesterase enzyme, which are similar to the native ligand donepezil. 3D-QSAR analysis revealed the importance of the alkyl group in positions 2 and 3 of the phenyl moiety for the activity. Overall, these findings suggested that compound 7c could be deemed a promising candidate for the management of Alzheimer's disease.


Assuntos
Doença de Alzheimer , Benzofuranos , Animais , Ratos , Inibidores da Colinesterase/farmacologia , Doença de Alzheimer/tratamento farmacológico , Donepezila , Acetilcolinesterase , Simulação de Acoplamento Molecular , Relação Quantitativa Estrutura-Atividade , Benzofuranos/farmacologia , Glutationa
4.
RSC Adv ; 13(27): 18496-18510, 2023 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-37346948

RESUMO

New 2-oxo-chromene-7-oxymethylene acetohydrazide derivatives 4a-d were designed and synthesized with a variety of bioactive chemical fragments. The newly synthesized compounds were evaluated as acetylcholinesterase (AChE) inhibitors and antioxidant agents in comparison to donepezil and ascorbic acid, respectively. Compound 4c exhibited a promising inhibitory impact with an IC50 value of 0.802 µM and DPPH scavenging activity of 57.14 ± 2.77%. Furthermore, biochemical and haematological studies revealed that compound 4c had no effect on the blood profile, hepatic enzyme levels (AST, ALT, and ALP), or total urea in 4c-treated rats compared to the controls. Moreover, the histopathological studies of 4c-treated rats revealed the normal architecture of the hepatic lobules and renal parenchyma, as well as no histopathological damage in the examined hepatic, kidney, heart, and brain tissues. In addition, an in vivo study investigated the amelioration in the cognitive function of AD-rats treated with 4c through the T-maze and beam balance behavioural tests. Also, 4c detectably ameliorated MDA and GSH, reaching 90.64 and 27.17%, respectively, in comparison to the standard drug (90.64% and 35.03% for MDA and GSH, respectively). The molecular docking study exhibited a good fitting of compound 4c in the active site of the AChE enzyme and a promising safety profile. Compound 4c exhibited a promising anti-Alzheimer's disease efficiency compared to the standard drug donepezil.

5.
RSC Med Chem ; 13(8): 929-943, 2022 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-36092142

RESUMO

Targeting the colchicine binding site of α/ß tubulin microtubules can lead to suppression of microtubule dynamics, cell cycle arrest and apoptosis. Therefore, the development of microtubule (MT) inhibitors is considered a promising route to anticancer agents. Our approach to identify novel scaffolds as MT inhibitors depends on a 3D-structure-based pharmacophore approach and docking using three programs MOE, Autodock and BUDE (Bristol University Docking Engine) to screen a library of virtual compounds. From this work we identified the compound 7-(3-hydroxy-4-methoxy-phenyl)-3-(3-trifluoromethyl-phenyl)-6,7-dihydro-3H-imidazo[4,5-b]pyridin-5-ol (6) as a novel inhibitor scaffold. This compound inhibited several types of cancer cell proliferation at low micromolar concentrations with low toxicity. Compound 6 caused cell cycle arrest in the G2/M phase and blocked tubulin polymerization at low micromolar concentration (IC50 = 6.1 ±0.1 µM), inducing apoptosis via activation of caspase 9, increasing the level of the pro-apoptotic protein Bax and decreasing the level of the anti-apoptotic protein Bcl2. In summary, our approach identified a lead compound with potential antimitotic and antiproliferative activity.

6.
ACS Omega ; 7(1): 1150-1164, 2022 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-35036778

RESUMO

DNA gyrase B is one of the enzyme targets for antimicrobial drug development, and its absence in mammals makes it a suitable target for the creation of safe antibacterial drugs. We identified six novel hits as DNA gyrase B inhibitors in the present study by employing 3D-pharmacophore structure-based virtual screening. The lead compounds complied with drug-likeness rules and lacked toxicity. Compound 4 (ZINC32858011) showed the highest inhibitory activity with an IC50 value of 6.3 ± 0.1 µM against the DNA gyrase enzyme. In contrast, the positive controls ciprofloxacin and novobiocin used in enzyme inhibition assay had IC50 values of 14.4 ± 0.2 and 12.4 ± 0.2 µM, respectively. The molecular docking of the six hits demonstrated that compounds 1, 2, 4, and 6 had suitable fitting modes inside the binding pocket. Molecular dynamics simulations were carried out for the six hits and the rmsd, rmsf, radius of gyration, and solvent accessible surface area parameters obtained from 100 ns molecular dynamics simulations for the six compounds complexed with a DNA gyrase B protein indicated that compound 4 (ZINC32858011) formed the most stable complex with DNA gyrase B. The binding free energy calculation with the MM-PBSA method suggested that the van der Waals interaction, followed by electrostatic force, played a significant role in the binding. Per-residue free binding energy decomposition showed that Ile78 contributed the most for the binding energy followed by Asn46, Asp49, Glu50, Asp73, Ile78, Pro79, Ala86, Ile90, Val120, Thr165, and Val167.

7.
J Biomol Struct Dyn ; 40(24): 13658-13674, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34676801

RESUMO

The outbreak caused by a coronavirus 2 has required quick and potential treatment strategies. The main protease enzyme Mpro plays an important role in the viral replication which renders it an important target for discovering SARS-CoV-2 inhibitors. In this study, 3D pharmacophore structure-based virtual screening and molecular docking were conducted using MOE and Bristol University Docking Engine (BUDE). Around 400,000 molecules of ZINC15 database were docked against the crystal structure of main protease, followed by 3D pharmacophore filtration. Six top-ranked hits (ZINC58717986, ZINC60399606, ZINC58662884, ZINC45988635, ZINC54706757 and ZINC17320595) were identified based on their strong spatial affinity and forming H-bonds with key residues H41, E166, Q189 and T190 of the binding pocket of Mpro SARS-CoV-2. The 6 hits subjected to molecular dynamics simulations for 100 ns followed by binding free energy calculations using MM-PBSA technique. Interestingly, three hits showed free binding energy (ΔGbinding) lower than tert-butyl N-[1-[(2S)-1-[[(2S)-4-(benzylamino)-3,4-dioxo-1-[(3S)-2-oxopyrrolidin-3-yl]butan-2-yl]amino]-3-cyclopropyl-1-oxopropan-2-yl]-2-oxopyridin-3-yl]carbamate (α-ketoamide 13 b) (ΔGbinding) -76.67 ± 0.5 kJ/mol which suggested their potential against SARS-CoV-2. The best binding free energy candidates, ZINC58717986 (ΔGbinding) -98.41 ± 0.7 kJ/mol. The second-best hit candidate, ZINC54706757 (ΔGbinding) -83.4 ± 0.6 kJ/mol and the third one ZINC17320595 (ΔGbinding) -78.85 ± 0.5 kJ/mol. Per residue decomposition free energy indicates H41, S46, H164, E166, D187, Q189 and Q192 are hot spot residues while residues M49, M165, L167 and P168 contribute to the hydrophobic interactions. The pharmacokinetic study suggests that the selected 6 hits possess drug-like properties. The 3D pharmacophore virtual screening, molecular dynamics and MM-PBSA approaches facilitated identification 3 promising hits with low free binding energy as SARS-CoV-2 inhibitors.Communicated by Ramaswamy H. Sarma.


Assuntos
COVID-19 , Humanos , Simulação de Acoplamento Molecular , Farmacóforo , SARS-CoV-2 , Peptídeo Hidrolases , Inibidores de Proteases/farmacologia
8.
Bioorg Med Chem Lett ; 43: 128099, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33984473

RESUMO

SARS-CoV-2 caused dramatic health, social and economic threats to the globe. With this threat, the expectation of future outbreak, and the shortage of anti-viral drugs, scientists were challenged to develop novel antivirals. The objective of this study is to develop novel anti-SARS-CoV-2 compounds with dual activity by targeting valuable less-mutated enzymes. Here, we have mapped the binding affinity of >500,000 compounds for potential activity against SARS-CoV-2 main protease (Mpro), papain protease (PLpro) and human furin protease. The enzyme inhibition activity of most promising hits was screened and tested in vitro on SARS-CoV-2 clinical isolate incubated with Vero cells. Computational modelling and toxicity of the compounds were validated. The results revealed that 16 compounds showed potential binding activity against Mpro, two of them showed binding affinity against PLpro and furin protease. Respectively, compounds 7 and 13 showed inhibition activity against Mpro at IC50 0.45 and 0.11 µM, against PLpro at IC50 0.085 and 0.063 µM, and against furin protease at IC50 0.29 µM. Computational modelling validated the binding affinity against all proteases. Compounds 7 and 13 showed significant inhibition activity against the virus at IC50 0.77 and 0.11 µM, respectively. Both compounds showed no toxicity on mammalian cells. The data obtained indicated that compounds 7 and 13 exhibited potent dual inhibition activity against SARS-CoV-2. The dual activity of both compounds can be of great promise not only during the current pandemic but also for future outbreaks since the compounds' targets are of limited mutation and critical importance to the viral infection.


Assuntos
Antivirais/farmacologia , Tratamento Farmacológico da COVID-19 , Peptídeo Hidrolases/metabolismo , SARS-CoV-2/efeitos dos fármacos , Antivirais/química , COVID-19/enzimologia , Humanos , Estrutura Molecular , Terapia de Alvo Molecular , Peptídeo Hidrolases/química , SARS-CoV-2/enzimologia
9.
RSC Adv ; 11(58): 36989-37010, 2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-35494381

RESUMO

The current work represents the design and synthetic approaches of a new set of compounds 6-10 bearing the 1,4-dimethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide scaffold. The biological evaluation revealed that most of the new compounds were promising selective dipeptidyl peptidase-IV (DPP-4) inhibitors and in vivo hypoglycemic agents utilizing linagliptin as a standard drug. The acute toxicity examination confirmed the safety profile of all compounds. Molecular docking studies related the significant DPP-4 suppression activity of compounds 9a, 10a, 10f, 10g to their nice fitting in the active pocket of DPP-4. In addition, the molecular dynamic study exhibited the stability of both 10a and 10g within the active site of DPP-4. The QSAR study showed that the difference between the predicted activities is very close to the experimental suppression effect. Moreover, both compounds 10a and 10g obeyed Lipinski's rule, indicating their efficient oral bioavailability. Compound 10a was radiolabeled, forming the 131I-SQ compound 10a to study the pharmacokinetic profile of this set of compounds. The biodistribution pattern hit the target protein since the tracer accumulated mainly in the visceral organs where DPP-4 is secreted in a high-level, thus with consequent stimulation of insulin secretion, leading to the target hypoglycemic effect.

10.
RSC Adv ; 11(61): 38616-38631, 2021 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-35493238

RESUMO

The emergent outbreak caused by severe acute respiratory syndrome coronavirus 2 continues spreading and causing huge social and economic disruption. Papain-like protease (PLpro) has a crucial role in the cleavage of viral polyproteins, and disruption of host responses. PLpro is considered an important goal for the development of SARS-CoV-2 inhibitors. ZINC101291108 (lead 1) and ZINC16449029 (lead 2) were identified as potent SARS-CoV-2 PLpro inhibitors with IC50 values of 0.085 µM and 0.063 µM, respectively. Molecular dynamics simulations (MD) were carried out for lead 1, 2 and several reported SARS-CoV-2 inhibitors. Analysis results of the simulations confirmed the stability of both compounds and showed that they adopted two confirmations along the simulation period. The per-residue decomposition results revealed that the key residues involved in inhibitor binding were E167, P247, P248, Y264, Y268 and Q269. H-bond analyses showed H-bonds with G266 and N267 and salt bridges with G209 and Y273, which are essential for strengthening the substrate-binding pocket. Both inhibitors showed hydrophobic interactions with the S4 site and BL2 loop residues. The RMSD of the BL2 loop with the two inhibitors was investigated, and the results showed that the Y268 and Q269 BL2 loop residues moved outward to accommodate the large size of lead 2. The van der Waals interaction was the main energy contribution that stabilized lead 2, while van der Waals and electrostatic interactions were the main energy contributions stabilizing lead 1. Rational design strategies were suggested to replace the 2-(2-hydroxybenzylidene) hydrazine moiety with naphthalene or nitrobenzene at the P4 position of lead 2 and introduce polar substituents as aniline and benzoate groups at position P1 to enhance hydrophobic interactions and H-bonds, respectively.

11.
Chem Biol Interact ; 333: 109318, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33186599

RESUMO

Antimicrobial resistance is at increasing risk worldwide since it is threatening the ability to control common infectious diseases, resulting in prolonged illness, disability, and death. Herein, we inspired by the effective plant phytochemical mechanisms evolved to overcome microbial pathogenesis and evolved resistance. Cuminaldehyde is previously reported as the main antibacterial component in Calligonum comosum essential oil. The toxicity of cuminaldehyde limits its medical application for human use. On the other hand, compared to cuminaldehyde, the plant total extract showed similar antibacterial activities, while maintained lower toxicity, although it contains 22 times less cuminaldehyde. Thus, we assumed that other components in the plant extracts specifically affect bacteria but not mammalian cells. Bioassay-guided fractionations combined with comparative metabolomics analysis of different plant extracts were employed. The results revealed the presence of bacterial species-specific phytochemicals. Cinnamyl linoleate and linoleic acid enhanced the antibacterial activities of cuminaldehyde and ampicillin against S. aureus including MRSA, while decanal and cinnamyl linoleate enhanced the activities against E. coli. Computational modeling and enzyme inhibition assays indicated that cinnamyl linoleate selectively bind to bacterial ribosomal RNA methyltransferase, an important enzyme involved in the virulence and resistance of multidrug resistant bacteria. The results obtained can be employed for the future preparation of pharmaceutical formula containing cinnamyl linoleate in order to overcome evolved multidrug resistance behaviors by microbes.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Caryophyllales/química , Desenho de Fármacos , Farmacorresistência Bacteriana/efeitos dos fármacos , Óleos Voláteis/química , Compostos Fitoquímicos/química , Antibacterianos/química , Materiais Biomiméticos/síntese química , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Linhagem Celular , Técnicas de Química Sintética , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Humanos
12.
Int J Mol Sci ; 21(23)2020 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-33256166

RESUMO

A series of 2-(1H-indol-3-yl)-5-substituted-1,3,4-oxadiazoles, 4a-m, were designed, synthesized and tested in vitro as potential pro-apoptotic Bcl-2 inhibitory anticancer agents based on our previously reported hit compounds. Synthesis of the target 1,3,4-oxadiazoles was readily accomplished through a cyclization reaction of indole carboxylic acid hydrazide 2 with substituted carboxylic acid derivatives 3a-m in the presence of phosphorus oxychloride. New compounds 4a-m showed a range of IC50 values concentrated in the low micromolar range selectively in Bcl-2 positive human cancer cell lines. The most potent candidate 4-trifluoromethyl substituted analogue 4j showed selective IC50 values of 0.52-0.88 µM against Bcl-2 expressing cell lines with no inhibitory effects in the Bcl-2 negative cell line. Moreover, 4j showed binding that was two-fold more potent than the positive control gossypol in the Bcl-2 ELISA binding affinity assay. Molecular modeling studies helped to further rationalize anti-apoptotic Bcl-2 binding and identified compound 4j as a candidate with drug-like properties for further investigation as a selective Bcl-2 inhibitory anticancer agent.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Desenho de Fármacos , Oxidiazóis/síntese química , Oxidiazóis/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Antineoplásicos/química , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Oxidiazóis/química , Ligação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
13.
Bioorg Med Chem Lett ; 30(24): 127658, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33130288

RESUMO

Human epidermal growth factor receptor (HER) is a family of multidomain proteins that plays important role in the regulation of several biological functions. HER2 is a member of HER that is highly presented in breast cancer cells. Here, we designed and synthesized a series of diaryl urea/thiourea compounds. The compounds were tested on HER2+ breast cancer cells including MCF-7 and SkBr3, compared to HER2- breast cancer cells including MDA-MB-231 and BT-549. Only compounds 12-14 at 10 µM showed selective anti-proliferative activity against MCF-7 and SkBr3 by 65-79%. Compounds 12-14 showed >80% inhibition of the intracellular kinase domain of HER2. The results obtained indicated that compounds 12-14 are selectively targeting HER2+ cells. The IC50 of compound 13 against MCF-7 and SkBR3 were 1.3 ± 0.009 and 0.73 ± 0.03 µM, respectively. Molecular docking and MD simulations (50 ns) were carried out, and their binding free energies were calculated. Compounds 12-14 formed strong hydrogen bond and pi-pi stacking interactions with the key residues Thr862 and Phe864. 3DQSAR model confirmed the role of 3-bromo substituent of pyridine ring and 4-chloro substituent of phenyl ring in the activity of the compounds. In conclusion, novel compounds, particularly 13 were developed selectively against HER2-expressing/overexpressing breast cancer cells including MCF7 and SkBr3.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Desenho de Fármacos , Receptor ErbB-2/metabolismo , Antineoplásicos/síntese química , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Terapia de Alvo Molecular , Receptor ErbB-2/análise
14.
Biochem J ; 477(13): 2489-2507, 2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32538426

RESUMO

Melanin is a dark color pigment biosynthesized naturally in most living organisms. Fungal melanin is a major putative virulence factor of Mucorales fungi that allows intracellular persistence by inducing phagosome maturation arrest. Recently, it has been shown that the black pigments of Rhizopus delemar is of eumelanin type, that requires the involvement of tyrosinase (a copper-dependent enzyme) in its biosynthesis. Herein, we have developed a series of compounds (UOSC-1-14) to selectively target Rhizopus melanin and explored this mechanism therapeutically. The compounds were designed based on the scaffold of the natural product, cuminaldehyde, identified from plant sources and has been shown to develop non-selective inhibition of melanin production. While all synthesized compounds showed significant inhibition of Rhizopus melanin production and limited toxicity to mammalian cells, only four compounds (UOSC-1, 2, 13, and 14) were selected as promising candidates based on their selective inhibition to fungal melanin. The activity of compound UOSC-2 was comparable to the positive control kojic acid. The selected candidates showed significant inhibition of Rhizopus melanin but not human melanin by targeting the fungal tyrosinase, and with an IC50 that are 9 times lower than the reference standard, kojic acid. Furthermore, the produced white spores were phagocytized easily and cleared faster from the lungs of infected immunocompetent mice and from the human macrophages when compared with wild-type spores. Collectively, the results suggested that the newly designed derivatives, particularly UOSC-2 can serve as promising candidate to overcome persistence mechanisms of fungal melanin production and hence make them accessible to host defenses.


Assuntos
Produtos Biológicos/metabolismo , Melaninas/biossíntese , Rhizopus/química , Ativação Enzimática/efeitos dos fármacos , Humanos , Melaninas/metabolismo , Estrutura Molecular , Monofenol Mono-Oxigenase/metabolismo , Fagocitose/fisiologia , Pironas/farmacologia , Relação Estrutura-Atividade
15.
Eur J Pharm Sci ; 148: 105327, 2020 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-32272212

RESUMO

Candida albicans is a common human fungal pathogen that causes disease ranging from superficial to lethal infections. C. albicans grows as budding yeast which can transform into hyphae in response to various environmental or biological stimuli. Although both forms have been associated with virulence, the hyphae form is responsible for the formation of multi-drug resistance biofilm. Here, new compounds were designed to selectively inhibit C. albicans hyphae formation without affecting human cells to afford sufficient safety. The newly designed 5-[3-substitued-4-(4-substituedbenzyloxy)-benzylidene]-2-thioxo-thiazolidin-4-one derivatives, named SR, showed very specific and effective inhibition activity against C. albicans hyphae formation. SR compounds caused hyphae inhibition activity at concentrations 10-40 fold lower than the concentration required to inhibit Candida yeast and bacterial growths. The anti-hyphae inhibition activities of SR compounds were via activation of the hyphae transcription repressor gene, TUP1. Correlation studies between the expression of TUP1 gene and the activity of SR compounds confirmed that the anti-C. albicans activities of SR compounds were via inhibition of hyphae formation. The newly designed SR compounds showed 10-40% haemolytic activity on human erythrocytes when compared to 100% haemolysis by 0.1% triton employed as positive control. Furthermore, theoretical prediction of absorption, distribution, metabolism, excretion, and toxicity (ADMET) of SR compounds confirmed their safety, efficient metabolism and possible oral bioavailability. With the minimal toxicity and significant activity of the newly-designed SR compounds, a future optimization of pharmaceutical formulation may develop a promising inhibitor of hyphal formation not only for C. albicans but also for other TUP1- dependent dimorphic fungal infections.


Assuntos
Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Candida albicans/efeitos dos fármacos , Proteínas Fúngicas/metabolismo , Hifas/efeitos dos fármacos , Biofilmes/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Regulação Fúngica da Expressão Gênica/efeitos dos fármacos , Hemólise , Humanos , Rodanina , Fatores de Transcrição/metabolismo
16.
Molecules ; 24(7)2019 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-30986908

RESUMO

The Bcl-2 protein has been studied as an anticancer drug target in recent years, due to its gatekeeper role in resisting programmed cancer cell death (apoptosis), and the design of BH3 domain mimetics has led to the clinical approval of Venetoclax (ABT-199) for the treatment of chronic lymphocytic leukaemia. In this work we extend our previous studies on the discovery of indole-based heterocycles as Bcl-2 inhibitors, to the identification of quinolin-4-yl based oxadiazole and triazole analogues. Target compounds were readily synthesized via a common aryl-substituted quinolin-4-carbonyl-N-arylhydrazine-1-carbothioamide (5a-b) intermediate, through simple variation of the basic cyclisation conditions. Some of the quinoline-based oxadiazole analogues (e.g. compound 6i) were found to exhibit sub-micromolar anti-proliferative activity in Bcl-2-expressing cancer cell lines, and sub-micromolar IC50 activity within a Bcl2-Bim peptide ELISA assay. The Bcl-2 targeted anticancer activity of 6i was further rationalised via computational molecular modelling, offering possibilities to extend this work into the design of further potent and selective Bcl-2 inhibitory heteroaromatics with therapeutic potential.


Assuntos
Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Quinolinas/química , Apoptose/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Ensaio de Imunoadsorção Enzimática , Compostos Heterocíclicos/química , Compostos Heterocíclicos/uso terapêutico , Humanos , Hidrocarbonetos Aromáticos/química , Hidrocarbonetos Aromáticos/uso terapêutico , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Oxidiazóis/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Triazóis/uso terapêutico
17.
Eur J Med Chem ; 168: 447-460, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30844608

RESUMO

A new series of 4-phenylcoumarin derivatives was synthesized starting from (2-oxo-4-phenyl-2H-chromen-7-yloxy) acetic acid hydrazide 3. Evaluation of the target compounds for their antiviral activity against hepatitis A virus revealed that the ethylthiosemicarbazide derivative 7b was the most potent virucidal agent (IC50 = 3.1 µg/ml, TI = 83). The Schiff's bases 14c and 14b demonstrated the highest virustatic effects against viral adsorption and replication, respectively (14c; IC50 = 8.5 µg/ml, TI = 88 and 14b; IC50 = 10.7 µg/ml, TI = 91). Furthermore, compounds 7b, 14b and 14c were tested against HAV 3C protease and showed significant inhibition effects (Ki = 1.903, 0.104 and 0.217 µM, respectively). The remarkable inhibitory effect expressed by the three target compounds against HAV 3C protease prompted us to expand our research on HRV 3C protease, a structurally related enzyme of the same family, and interestingly, the three target compounds displayed significant inhibitory effect against HRV 3C protease (IC50 = 16.10, 4.13 and 6.30 µM, respectively). Moreover, the active compounds 7b, 14b and 14c were docked within the pocket site of HAV 3C protease (PDB code: 2HAL) illustrating a strong H-profile with the key amino acids Gly170 and Cys172 similar to the co-crystallized ligand. Furthermore, 3D-pharmacophore and quantitative structure activity relationship (QSAR) models were generated to explore the structural requirements for the observed antiviral activity.


Assuntos
Antivirais/farmacologia , Cumarínicos/farmacologia , Desenho de Fármacos , Vírus da Hepatite A/efeitos dos fármacos , Inibidores de Proteases/farmacologia , Proteínas Virais/antagonistas & inibidores , Proteases Virais 3C , Antivirais/síntese química , Antivirais/química , Cumarínicos/síntese química , Cumarínicos/química , Cisteína Endopeptidases/metabolismo , Relação Dose-Resposta a Droga , Vírus da Hepatite A/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Relação Quantitativa Estrutura-Atividade , Proteínas Virais/metabolismo
18.
Bioorg Chem ; 85: 253-273, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30641320

RESUMO

New thiazolylpyrazolyl coumarin derivatives were synthesized and tested for their anticancer potential in vitro against five different human cell lines, including breast MCF-7, lung A549, prostate PC3, liver HepG2 and normal melanocyte HFB4. Breast carcinoma revealed higher sensitivity towards compounds 7a, 8c, 9b, 9c and 9d with IC50 values ranging from 5.41 to 10.75 µM in comparison to the reference drug doxorubicin (IC50 = 6.73 µM). In addition, no noticeable toxicity was exhibited towards normal cells HFB4. Moreover, in vitro studies of the VEGFR-2 inhibition in human breast cancer MCF-7 cell line for the promising cytotoxic compounds showed that compounds 7a, 8c, 9b, 9c and 9d were potent inhibitors at low micromolar concentrations (IC50 = 0.034-0.582 µM) compared to the reference drug, sorafenib (IC50 = 0.019 µM). Several theoretical and experimental studies were done to reveal the molecular mechanisms that control breast carcinoma metastasis. The mechanistic effectiveness in cell cycle progression, apoptotic induction and gene regulation were assessed for the promising compound 9d due to its remarkable cytotoxic activity against MCF-7 and significant VEGFR-2 inhibition. Flow cytometeric analysis showed that compound 9d induced cell growth cessation at G2/M phase and increased the percentage of cells at pre-G1 phase that stimulates the apoptotic death of MCF-7 cells. Furthermore, real time PCR assay illustrated that compound 9d up regulated p53 gene expression and elevated Bax/Bcl-2 ratio which confirmed the mechanistic pathway of compound 9d. Moreover, the apoptotic induction of breast cancer cells MCF-7 was enhanced effectively through activation of caspases-7 and 9 by compound 9d. On the other hand, a set of in silico methods such as molecular docking, molecular dynamics simulation, QSAR analysis as well as ADMET analysis was performed in order to study the protein-ligand interactions and the relationship between the physicochemical properties and the inhibitory activity of the promising compounds 7a, 8c and 9d. Based on the aforementioned findings, compound 9d could be considered as effective apoptosis modulator and promising lead for future development of new anti-breast cancer agents.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Cumarínicos/farmacologia , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Caspase 7/metabolismo , Caspase 9/metabolismo , Domínio Catalítico , Linhagem Celular Tumoral , Cumarínicos/síntese química , Cumarínicos/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Pirazóis/síntese química , Pirazóis/metabolismo , Pirazóis/farmacologia , Relação Quantitativa Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/metabolismo , Tiazóis/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
19.
Mini Rev Med Chem ; 19(3): 250-269, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-28847268

RESUMO

OBJECTIVE: Inhibition of dipeptidyl peptidase IV (DPP-4) is currently one of the most valuable and potential chemotherapeutic regimes for the medication of Type 2 Diabetes Mellitus (T2DM). METHOD: Based on linagliptin, this study discusses the design, synthesis and biological evaluation of spiro cyclohexane-1,2'-quinazoline scaffold hybridized with various heterocyclic ring systems through different atomic spacers as a highly potent DPP-4 inhibitors. DPP-4 enzyme assay represented that most of the target compounds are 102-103 folds more active than the reference drug linagliptin (IC50: 0.0005-0.0089 nM vs 0.77 nM; respectively). Moreover, in vivo oral hypoglycemic activity assay revealed that most of the tested candidates were more potent than the reference drug, sitagliptin, producing rapid onset with long duration of activity that extends to 24 h. Interestingly, the derivatives 11, 16, 18a and 23 showed evidence of mild cytochrome P450 3A4 (CYP3A4) inhibition (IC50; > 210 µM) and their acute toxicity (LD50) was more than 1.9 gm/kg. Molecular simulation study of the new quinazoline derivatives explained the obtained biological results. CONCLUSION: Finally, we conclude that our target compounds could be highly beneficial for diabetic patients in the clinic.


Assuntos
Cicloexanos/química , Dipeptidil Peptidase 4/metabolismo , Desenho de Fármacos , Quinazolinas/síntese química , Quinazolinas/farmacologia , Compostos de Espiro/química , Animais , Técnicas de Química Sintética , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/síntese química , Inibidores do Citocromo P-450 CYP3A/química , Inibidores do Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/farmacologia , Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/química , Inibidores da Dipeptidil Peptidase IV/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Dose Letal Mediana , Simulação de Acoplamento Molecular , Conformação Proteica , Quinazolinas/química , Quinazolinas/metabolismo , Ratos , Relação Estrutura-Atividade
20.
Mini Rev Med Chem ; 19(15): 1255-1275, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29600761

RESUMO

Objective & Methodology: New hybrids of thiopyrimidine-five/six heterocyclic rings were synthesized and in vitro evaluated for their antiproliferative activity against three human cancer cell lines, namely HCT116 (human colorectal carcinoma), PC-3 (human prostate adenocarcinoma) and HepG2 (human liver carcinoma) cell lines. The most potency was elicited by the target candidates against the viability of HCT116 cell lines. It was higher than that obtained by the positive control 5-Fluorouracil (IC50 range; 0.11-0.49 µM, IC50, 5-FU; 1.10 µM). Results: Cell cycle analysis and apoptosis activation revealed that compound 20 induced G2/M phase arrest and apoptosis in HCT116 cells. In addition, compound 20 activates the caspases-9 and -3, a process which might mediate the apoptosis of HCT116 cells. Quantitative structure activity relationship study was done and revealed a high predictive power R2 suggesting goodness of the models. Conclusion: Furthermore, there is a good agreement between the observed pIC50 and the predicted pIC50 values, in addition, the low RMSD and standard error values indicate the accuracy of the model. Antimicrobial evaluation revealed that some of these compounds exhibited significant activities against the tested pathogenic bacteria and fungi, wherein compounds 7a, 14, 15a, 21a, produced the most potent and broad spectrum antibacterial and antifungal potency that was equivalent to that revealed by Vibramycin and Ketoconazole (MIC; 125 µg/mL). Moreover, compounds 15a, 21c, investigated dual potent antimicrobial and anticancer activity.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Antifúngicos/síntese química , Antifúngicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Pirimidinas/farmacologia , Relação Quantitativa Estrutura-Atividade , Compostos de Sulfidrila/farmacologia , Antibacterianos/química , Antifúngicos/química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Fungos/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/química
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