ABSTRACT
The need for new chemotherapeutics to overcome development of resistance merits research to discover new agents. Benzocaine derivatives are essential compounds in medicinal chemistry due to their various biological activities including antibacterial and anticancer activities. Therefore, this study focuses on the synthesis of new benzocaine derivatives 3a-e, 6, 7a and 7b, 8, 10-14, and 16a-d and their in vitro evaluation as antibacterial agents against gram +ve and -ve strains and as anticancer agents against HepG-2, HCT-116, and MCF-7 human cancer cell lines. The obtained results demonstrated that thiazolidines 6 and 7b showed higher antibacterial and anticancer activity in comparison with the reference drugs. In addition, 6 and 7b showed high potency as inhibitors toward their biological targets, that is DNA gyrase and human topoisomerase IIα, as compared to the reference standard drugs novobiocin and etoposide, respectively. Molecular docking demonstrated that both compounds could identify the active site of their target enzymes and develop effective binding interactions. Absorption, distribution, metabolism and elimination (ADME) and drug-likeness predictions of both compounds showed that they both have good ADME profiles and no structural alerts that might cause toxicity. Based on this, 6 and 7b could serve as lead compounds for the design of more potent antibacterial and anticancer agents.
Subject(s)
Antineoplastic Agents , Benzocaine , Anti-Bacterial Agents/chemistry , Humans , Molecular Docking Simulation , Molecular Structure , Structure-Activity RelationshipABSTRACT
BACKGROUND: Azolopyrimidines are imposed on the arena of drugs treated for cancer. The urgent need to discover new selective anticancer agents, paved the way to explore the antitumor significance of such fused systems. From the synthetic point of view, Microwave facilitated technique for synthesis is very strongly associated with green method in chemistry field. AIM: Our aim is to synthesize bioactive compounds using docking simulation run by MOE program to explore the binding mode of the most active enzyme inhibitor among the target compounds. METHODS: In addition to the use of conventional heating, the MARS system of CEM utilized for Microwave irradiation that is equipped with a multi-mode platform with a magnetic stirring plate and a rotor that allows the parallel processing of many vessels per batch. All the synthesized compounds were tested for their anticancer activity against hepatic cancer (HepG-2), breast cancer (MCF-7) and colon cancer (HCT-116). Screening against the cancer cell lines was performed, using doxorubicin as a reference drug. Docking studies were conducted using MOE software. RESULTS: A novel series of fluorinated fused-pyrimidine namely, pyrazolopyrimidine, triazolopyrimidine and pyrimidobenzimidazole were designed and synthesized conventionally and under microwave irradiations. The mechanistic pathways as well as the structure of all products were debated and demonstrated based on all possible spectral data. In-vitro examination of the novel prepared derivatives versus the three different human cancer cell lines [hepatic cancer (HepG-2), breast cancer (MCF-7) and colon cancer (HCT-116)] was evaluated to estimate their actual activity. CONCLUSION: We have developed a simple, facile, and efficient procedure for the formation of new series of azolopyrimidines. All spectra of all products were investigated deliberately to confirm their structures. The anti-cancer activity has been examined against three cancer cell lines e.g. HepG-2, MCF-7 and HCT116. Molecular modeling study was carried out in order to rationalize the in vitro anti-tumor results.
Subject(s)
Antineoplastic Agents/pharmacology , Benzimidazoles/pharmacology , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Triazoles/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/metabolism , Benzimidazoles/chemical synthesis , Benzimidazoles/metabolism , Catalytic Domain , Cell Line, Tumor , Cyclin-Dependent Kinase 2/antagonists & inhibitors , Cyclin-Dependent Kinase 2/chemistry , Cyclin-Dependent Kinase 2/metabolism , Drug Screening Assays, Antitumor , Humans , Microwaves , Molecular Docking Simulation , Molecular Structure , Protein Binding , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacology , Pyrazoles/chemical synthesis , Pyrazoles/metabolism , Pyrimidines/chemical synthesis , Pyrimidines/metabolism , Structure-Activity Relationship , Temperature , Triazoles/chemical synthesis , Triazoles/metabolismABSTRACT
The discovery of the antiproliferative potential of tranilast prompted additional studies directed at understanding the mechanisms of tranilast action. Its inhibitory effect on cell proliferation depends principally on the capacity of tranilast to interfere with transforming growth factor beta (TGFßR1) signaling. This work summarizes design, synthesis and biological evaluation of sixteen novel tranilast analogs on different tumors such as PC-3, HepG-2 and MCF-7 cell lines. The in vitro cytotoxicity was evaluated using MTT assay showed that, twelve compounds out of sixteen showed higher cytotoxic activities (IC50's 1.1-6.29 µM), than that of the reference standard, 5-FU (IC50 7.53 µM). The promising cytotoxic hits (4b, 7a, b and 14c-e), proved to be selective to cancer cells when their cytotoxicity's are examined on human normal cell line (WI-38). Then they are investigated for their possible mode of action as TGFßR1 inhibitors; remarkable inhibition of TGFßR1 by these hits was observed at the range of IC50 0.087-3.276 µM. The cell cycle analysis of the most potent TGFßR1 inhibitor, 4b revealed cell cycle arrest at G2/M phase on prostate cancer cells. Additionally, it is clearly indicated apoptosis induction at Pre-G1 phase, this is substantiated by significant increase in the expression on the tumor suppressor gene, p53 and up regulation the level of apoptosis mediator, caspase-3. In addition, in silico study was performed for validating the physicochemical and ADME properties which revealed that, all compounds are orally bioavailable with no side effects complying with Lipinski rule. The proposed mode of action can be further explored on the light of molecular modeling simulation of the most potent compounds, 4b and 14e which were docked into the active sites of TGFßR1 to predict their affinities toward the receptor.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Design , Molecular Docking Simulation , Protein Kinase Inhibitors/pharmacology , Receptor, Transforming Growth Factor-beta Type I/antagonists & inhibitors , ortho-Aminobenzoates/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Cycle/drug effects , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Receptor, Transforming Growth Factor-beta Type I/metabolism , Structure-Activity Relationship , Tumor Cells, Cultured , ortho-Aminobenzoates/chemical synthesis , ortho-Aminobenzoates/chemistryABSTRACT
Urease enzyme is a virulence factor that helps in colonization and maintenance of highly pathogenic bacteria in human. Hence, the inhibition of urease enzymes is well-established to be a promising approach for preventing deleterious effects of ureolytic bacterial infections. In this work, novel thiobarbiturate derivatives were synthesized and evaluated for their urease inhibitory activity. All tested compounds effectively inhibited the activity of urease enzyme. Compounds 1, 2a, 2b, 4 and 9 displayed remarkable anti-urease activity (IC50 = 8.21-16.95 µM) superior to that of thiourea reference standard (IC50 = 20.04 µM). Moreover, compounds 3a, 3g, 5 and 8 were equipotent to thiourea. Among the tested compounds, morpholine derivative 4 (IC50 = 8.21 µM) was the most potent one, showing 2.5 folds the activity of thiourea. In addition, the antibacterial activity of the synthesized compounds was estimated against both standard strains and clinical isolates of urease producing bacteria. Compound 4 explored the highest potency exceeding that of cephalexin reference drug. Moreover, biodistribution study using radiolabeling approach revealed a remarked uptake of 99mTc-compound 4 into infection induced in mice. Furthermore, a molecular docking analysis revealed proper orientation of title compounds into the urease active site rationalizing their potent anti-urease activity.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Drug Design , Enzyme Inhibitors/chemistry , Thiobarbiturates/chemistry , Urease/antagonists & inhibitors , Animals , Anti-Bacterial Agents/metabolism , Anti-Bacterial Agents/pharmacology , Binding Sites , Catalytic Domain , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacology , Hydrogen-Ion Concentration , Isotope Labeling , Klebsiella pneumoniae/drug effects , Male , Mice , Microbial Sensitivity Tests , Molecular Docking Simulation , Organotechnetium Compounds/chemistry , Proteus vulgaris/drug effects , Structure-Activity Relationship , Thiobarbiturates/metabolism , Thiobarbiturates/pharmacology , Thiourea/analogs & derivatives , Thiourea/metabolism , Thiourea/pharmacology , Tissue Distribution , Urease/metabolismABSTRACT
Fumarate diester 3 was synthesized upon reacting anthranilic acid with diethylacetylenedicarboxylate. Compound 3 was reacted with different nucleophiles in mild reaction conditions. Selected reaction routes that afforded products 6, 9, 10, 11, and 12 were explained. The estimated mechanism for the reaction of 3 with ethylenediamine to afford 9 was proved by X-ray single-crystal and retro-synthetic reaction. Acetyl anthranilic acid was utilized with zinc and copper to afford the organometallic compounds 14a and 14b, respectively. Three single crystals were afforded for 3, 9 and the organocopper complex 14b. Target compounds were screened for their inhibitory potential against urease enzyme. Most compounds were more potent than thiourea as standard inhibitor, considering that oxopiperazine 9 exhibited double the activity: IC50 = 8.16 ± 0.65 µM (thiourea IC50 = 20.04 ± 0.33 µM). Docking studies were in agreement with the in vitro enzyme assay.
Subject(s)
Alkynes/pharmacology , Enzyme Inhibitors/pharmacology , Organometallic Compounds/pharmacology , Urease/antagonists & inhibitors , ortho-Aminobenzoates/pharmacology , Alkynes/chemistry , Canavalia/enzymology , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Models, Molecular , Molecular Structure , Nitrogen Compounds , Organometallic Compounds/chemical synthesis , Organometallic Compounds/chemistry , Structure-Activity Relationship , Urease/metabolism , ortho-Aminobenzoates/chemistryABSTRACT
A series of twenty five new thiobarbituric acid derivatives, viz. 3a-h, 4-7, 8a-c, 9, 10a-c, 11 and 12a-d, were designed and synthesized as potential cytotoxic agents. In-vitro screening of the new compounds against the three human cancer cell lines Caco-2, HepG-2 and MCF-7 was performed to assess their intrinsic activity. Compound 12d exhibited potent sub-micromolar activity against HepG-2 and MCF-7 (IC50â¯=â¯0.07 and 0.08⯵M, respectively). In-silico pharmacophore modelling of this chemotype compounds disclosed a five features' pharmacophore model representing essential steric and electronic fingerprints essential for activity. Finally, a 2D-QSAR model was devised to quantitatively correlate the 2D molecular feature descriptors of this series of thiobarbiturates with their cytotoxic activity against MCF-7. Finally, in silico evaluation of the physicochemical and ADME properties of these derivatives was performed.
Subject(s)
Computer Simulation , Cytotoxins/chemical synthesis , Quantitative Structure-Activity Relationship , Thiobarbiturates/chemical synthesis , Caco-2 Cells , Cytotoxins/toxicity , Drug Evaluation, Preclinical/methods , Hep G2 Cells , Humans , MCF-7 Cells , Thiobarbiturates/toxicityABSTRACT
Ethyl (6,7-dimethyl-2-oxo-3,4-dihydroquinoxalin-3-yl)acetate and ethyl (6-methyl-2-oxo-3,4-dihydroquinoxalin-3-yl)acetate (1a,b), 3-methylquinoxalin-2(1H)-one (4) and 1,4-dihydroquinoxaline-2,3-dione (11) were the starting precursors for nine novel quinoxaline compounds, 3a, 6, 10, 13, 15, 16, 17, 18, and 20, via adopting different nucleophilic reactions. The synthesized compounds were tested for their antiviral activity against HCV, HBV, HSV-1, and HCMV. Concomitantly, their safety profile was investigated as well as their selectivity against the viral strains. The Virology Unit at the University of Alabama recorded that two compounds, i.e., 1a and 20, exhibited highly potent activity against HCMV with lower IC50 values (<0.05 µM) compared to ganciclovir (IC50 = 0.59 µM). Compounds 1a and 20 also exhibited low cytotoxicity together with a high selectivity index.
Subject(s)
Antiviral Agents/pharmacology , Cytomegalovirus/drug effects , Hepacivirus/drug effects , Hepatitis B virus/drug effects , Herpesvirus 1, Human/drug effects , Quinoxalines/pharmacology , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Dose-Response Relationship, Drug , Microbial Sensitivity Tests , Molecular Structure , Quinoxalines/chemical synthesis , Quinoxalines/chemistry , Structure-Activity RelationshipABSTRACT
Treatment of 3-phenyl-1,3-thiazolidin-4-one derivative 1 with phenylisothiocyanate in DMF, in the presence of potassium hydroxide, at room temperature gave the non-isolable potassium salt 2. The in-situ reaction of 2 with differently substituted N-aryl hydrazonoyl chlorides 3, 7a-d and 14a-d afforded the corresponding 2-(pyrazolyl)thiazolylimino-5-(thiadiazolylidene)thiazolidin-4-one derivatives 6, 10a-d and 17a-d, respectively. Reaction of 2 with further α-haloketones yielded the 4-(pyrazolyl)thiazolylimino-bis-thiazolidine derivatives 22, 25 and 26. Single crystal X-ray analysis was used in structure elucidation of the products. The in-vitro antiviral screening against four viruses (Poliovirus, Influenza A (H1N1) virus, Hepatitis B virus and Hepatitis C virus) for the obtained compounds was examined. Structure activity relationship (SAR) was also studied. The goal of the work was achieved in discovering a very active compound 10a as anti HCV agent (EC50 0.56 µM).
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Hepacivirus/drug effects , Hepatitis B virus/drug effects , Influenza A Virus, H1N1 Subtype/drug effects , Poliovirus/drug effects , Thiadiazoles/pharmacology , Thiazoles/pharmacology , Antiviral Agents/chemistry , Dose-Response Relationship, Drug , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Thiadiazoles/chemical synthesis , Thiadiazoles/chemistry , Thiazoles/chemical synthesis , Thiazoles/chemistryABSTRACT
N-(4-(Pyrazol-4-yl)thiazol-2-yl)-N'-phenylthiourea derivative 2 was synthesized and then treated with variety of hydrazonoyl chlorides under basic condition at reflux to afford the corresponding 2-(4-(pyrazol-4-yl)thiazol-2-ylimino)-1,3,4-thiadiazole derivatives 6, 10a-e and 17a-e. Reaction of 2 with ethyl chloroacetate and with 3-chloro-2,4-pentanedione gave the thiazolidin-4-one 22 and 1,3-thiazole 25 derivatives, respectively. Condensation of thiazolidin-4-one 22 with aldehydes gave their 5-arylidene derivatives 23a-f. Most of the synthesized compounds were tested for anticancer activity against human hepatocelluar carcinoma HepG2, human breast cancer MCF-7 and human lung cancer A549. Their SAR was studied and variously affected by the electronic factor of electron donating and withdrawing groups. Many of the tested compounds showed moderate to high anticancer activity.
Subject(s)
Antineoplastic Agents/pharmacology , Pyrazoles/chemistry , Thiadiazoles/pharmacology , Thiazoles/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Hep G2 Cells , Humans , MCF-7 Cells , Molecular Structure , Structure-Activity Relationship , Thiadiazoles/chemical synthesis , Thiadiazoles/chemistry , Thiazoles/chemical synthesis , Thiazoles/chemistryABSTRACT
Regioselective 1,3-dipolar cycloaddition of nitrilimines with 5-arylidene-2-arylimino-4-thiazolidinones and with 2-(4-arylidene)thiazolo[3,2-a]benzimidazol-3(2H)-ones afforded the corresponding 1,3,4-triaryl-5-N-arylpyrazole-carboxamides and pyrazolylbenzimidazoles. All reactions were carried out under conventional thermal heating and/or microwave irradiation. Both the pyrazole-5-carboxamides and pyrazolylbenzimidazoles were examined for their in-vitro anti-tumor activities against two tumor cell lines, Hep-2 and colon CaCo-2. Most of the obtained compounds exhibited significant activity against CaCo-2 and Hep-2 cell lines.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Microwaves , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Antineoplastic Agents/chemistry , Benzimidazoles/chemistry , Caco-2 Cells , Humans , Inhibitory Concentration 50 , Pyrazoles/chemistry , Stereoisomerism , Substrate SpecificityABSTRACT
The key precursor E-3-(N,N-dimethylamino)-1-(3-methylthiazolo[3,2-a]benzimidazol-2-yl)prop-2-en-1-one 4 was synthesized in good yield using Gold's reagent. The reaction of enaminone 4 with 5-amino-3-aryl-1-phenylpyrazoles 5a, b in refluxing acetic acid in the presence of sulphuric acid, yielded pyrazolo[3,4-b]pyridines 7a, b. Similarly, pyrazolo[1,5-a]pyrimidines 10a, b and 14a-f were prepared by reaction of enaminone 4 with 5-amino-1H-pyrazoles 8a, b and 12a-f, respectively. The structure of pyrazolo[1,5-a]pyrimidine 10b was determined by X-ray diffraction. The synthesized compounds were tested for their in-vitro antitumor activity against the colon cancer cell line CaCo-2; their cytotoxicity against the normal fibroblast cell line BHK was explored as well. Some of the tested compounds exhibited cell growth inhibitory activity. The significant antitumor activity of compound 14f against the CaCo-2 cell line (IC(50 )= 0.5 microg/mL) was coupled with a lower toxicity against BHK (IC(50 )= 2.3 microg/mL).