Letters in Drug Design & Discovery - Volume 15, Issue 12, 2018

Background: CDK2 shows a fundamental role as a controller of cell growing, which makes it as one of the goals of anticancer inhibitors. Methods: The current study participated in design (docking and binding energy), which used to select the promising proposed compounds, synthesis of novel diverse 14 pyrido[2,3-d]pyrimidine derivatives and biological studies of the prepared compounds as promising anticancer agents aiming CDK2. All the fresh generated compounds were scanned for their anticancer activity versus MCF-7 and CaCO2 and 14 compounds were found to be active. Compounds 6c and 8d displayed expressive activity with IC50 values 7.4 and 5.5 on MCF-7 respectively. The created compounds were submitted to enzyme inspection (CDK2) for assigning their inhibitory activity. Results: The initial results showed that compound 8d, which demonstrates potent inhibitory activity towards tumor development and powerful inhibitions of CDK2 enzyme (89% inhibition) could be utilized as a lead candidate. The products were characterized by IR, 1H NMR, 13CNMR and MS. Conclusion: Preliminary bioassays indicated that most of the compounds exhibited very good antitumor activity and powerful inhibitions of CDK2 enzyme.

Background: Metal organic compounds have attracted considerable attention since the advent of Salvarsan, a metal organic compound for the treatment of syphilis. Ferrocene as an effective phenyl bioisostere is becoming a viable platform for drug design by virtue of its redox properties, high lipophilicity and three-dimensional metallocene unit, which may lead to some changes in selectivity toward biological targets compared with phenyl or alkyl groups. Therefore, ferrocene seems to an appropriate candidate for improving the antioxidant activity of drugs. Methods: We synthesized four ferrocenyl-containing curcumin analogues by introducing ferrocenyl groups into the active methylene groups to obtain higher antioxidant activity than the parent ferrocene- substituted curcumin analogues, and their antioxidant activities were evaluated in 2, 2′- azobis (2-amidinopropane hydrochloride) (AAPH) and Cu2+/glutathione(GSH) -induced oxidation of DNA, and in trapping 2, 2′-diphenyl-1-picrylhydrazyl (DPPH), 2, 2′-azinobis(3-ethylbenzothiazoline- 6-sulfonate) cationic radicals (ABTS+•) and galvinoxyl radicals. Results: These ferrocenyl-containing curcumin analogues can protect DNA against Cu2+/GSHinduced oxidation, and scavenge 5.7, 6.9, 5.5 and 5.3 radicals in protecting DNA against AAPHinduced oxidation. Compounds (3)~(5) can trap more DPPH, ABTS+• and galvinoxyl radicals than compound (6). The substituents and iron atoms play an antioxidant role in ferrocenyl-containing curcumin analogues. Conclusion: The introduction of ferrocenyl group results in a higher antioxidant activity than the traditional hydroxyl-involved curcumin analogues. The ferrocenyl group is a powerful antioxidative group that could be used to modify natural antioxidants. The electron-accepting group attaching to the phenyl-group could further increase the antioxidant activity. Ferrocene-containing curcumin analogues show higher activities in quenching radicals and protecting DNA against radical-induced oxidation. Therefore, the introduction of ferrocenyl group into the natural antioxidant may contribute to increase the antioxidant activity.

Background: Due to the increase of multidrug-resistant microorganisms, the search for biologically active molecules does not stop. In the present study, we developed the effective QSAR model which allows a quick search of new potential Staphylococcus aureus inhibitors in the series of quaternary phosphonium salts. A number of the most promising 1,3-oxazol-4-yltriphenylphosphonium derivatives with predicted activities were synthesized and examined to confirm their antibacterial properties and the accuracy of the forecast. Furthermore, the toxicity of the investigated compounds was evaluated. Methods: The predictive QSAR model was developed using Artificial Neural Network approach. Antibacterial properties of the investigated compounds were performed using standard disk diffusion method. The toxicity of the compounds was determined in vivo using zebrafish (Danio rerio) and in vitro on acetylcholinesterase (AChE) enzyme as the test models. Results: The predictive ability of the regression model was tested by cross-validation, giving the cross-validated coefficient q2=0.82. Derivatives of 1,3-oxazol-4-yltriphenylphosphonium salts predicted as active were synthesized and screened for their antibacterial activities. All compounds demonstrated antibacterial activity according to the prediction. The toxicity tests indicated that all investigated samples were less toxic than well-known cationic surfactants. Conclusion: The most promising compound 2b exhibited strong antibacterial activity together with low toxicity and can be considered as a new efficient biocidal agent for future investigation. In addition, the proposed QSAR model can be used for predicting and designing novel potential S. aureus inhibitors among ionic liquids/salts.

Background: A variety of synthetic amidrazones are endowed with antitumor activity. Examples include N1-(thien-3-yl)amidrazone-2-carboxylates that exhibit high potency against breast cancer (MCF-7) and leukemia (K562) cell lines. These results prompted us to design and examine a new set of isomeric N1-(thienyl)amidrazone. Methods: The synthesis of the targeted N1-(thien-4-yl)amidrazone-4-carboxylates 7a-n is achieved via interaction of the appropriate (N-substituted)piperazine with nitrile imine 1,3 dipole (generated in situ from the N1-(thien-4-yl)hydrazonoyl chloride precursor by the action of NEt3). Results: Among the tested compounds 7a-n, the amidrazone (7m) incorporating N4-(pyridin-2- yl)piperazine moiety was the most active against leukemia (K562) with IC50 value of 1.02 μM. Docking studies showed that 7m binds with the oncogenic protein kinase Bcr-Abl. Noteworthy, compound 7m shows negligible cytotoxic effect on human normal fibroblast cells. Conclusion: Compound 7m could probably act as a prospective lead structure for development of new synthetic N1-(thienyl)amidrazones against leukemia (K562).

Background: Thiamine hydrochloride is a vital nutrient for development, growth and variety of other body functions. It is also used as a co-factor for several enzymatic reactions. An early study showed that thiamine can form ionic salt with metals such as [Th]2+[MX4]2-, [Th]2+([MX3]-)2, or [Th+]2[MX4]2- (M = Zn2+ Co2+, Ni2+ when X = Cl-, Br- and Th = thiamine). Methods: In this study, thiamine hydrochloride reacts with iron (II), zinc (II) and cobalt (II) to form [Fe6L2(NH3)12(H2O)12](SO4)6.10H2O, [Zn3L(H2O)6Cl3]Cl3 and [Co3L(H2O)6Cl3]Cl3 complexes, respectively. Antimicrobial activity was carried out by agar well diffusion method. Results: Structures of these complexes were characterized by different methods like IR, EIMS and CHN analysis. The ligand and their complexes were screened for antimicrobial activities. The maximum antibacterial activity against Gram positive bacterial strains (C. xerosis 23 mm, S. aureus, and S. saprophyticus, 22 mm) was observed by Th-Zn complex. The highest antibacterial activity against Gram negative bacterial strains was observed as follows: Th-Zn complex (25 mm, S. dysenteriae), Th-Co complex (20 mm, S. paratyphi B and vibrio) and Th-Fe complex (20 mm, E. aerogene). All complexes were found to be inactive against A. flavus, A. niger. C. tropicalis, Penicillium spp., Rhizopus spp., and S. cerevisiae fungal strains, while Th-Fe and Th-Co complexes showed very weak activity against C. albican (4mm). Conclusion: In synthetic compounds, Th-Zn complex is responsible for good antibacterial activity against Gram positive bacterial strains. However, Th-Zn, Th-Co, and Th-Fe complexes are suitable for Gram negative strains. All compounds showed no activity against tested fungal strains. Consequently, these complexes might have good potential for further studies as antiobiotics.

Background: Breast cancer is the most frequent cancer among women. Chemotherapy is necessary for treating metastatic disease and represents an important therapeutic approach, although antineoplastic drugs have high toxicity and may be limited by the development of drug resistance. These problems impose an urgent need to discover new anticancer agents and, so, arylsulfonylhydrazone analogues were designed, synthesized, and evaluated with regard to their cytotoxic activity against breast cancer cells in order to identify novel potential antitumor agents. Methods: Synthesis was performed as previously described by Fernandes and co-workers. Cytotoxicity of sulfonylhydrazones against MDA-MB-231, MCF-7 and 3T3 cells was evaluated by MTT method. Apoptotic effects was verified by Annexin-V/PI assay, Hoechst stain and propidium iodide stain. Molecular modeling was executed using Spartan'10 version 1.1.0. Geometry optimization was performed by the MMFF, PM6 and Hartree-Fock 3-31G* methods and electronic and lipophilic properties were computed. Results: Thirteen analogues were synthesized, which 3f and 4f were cytotoxic against evaluated breast cancer cells. The most promising compound, 3f, showed IC50 values equal to 104.6 and 142.4 μM for MDA-MB-231 and MCF-7, respectively. 3f induced apoptosis, causing phosphatidylserine externalization, pyknosis, and cell cycle arrest in the G0/G1 phase in MDA-MB-231 breast cancer cells. Furthermore, 3f was selective for tumor cells when compared to 3T3 fibroblasts. Structure- activity relationship suggests that introduction of a benzodioxol group increased cytotoxicity and superior lipophilicity may be related to superior activity. Conclusion: Sulfonylhydrazone analogues presented good activity against breast cancer cells by inducing apoptosis and might be a promising scaffold to further molecular modifications persuing more effective antitumoral agents.

Background: Hetero atom containing compounds are well studied class of organic compounds exhibits variety of properties and applications. Design and synthesis of new heterocyclic compounds are always of great interest in synthetic and medicinal organic chemistry. Benzothiazole or 2-aminobenzothiazole scaffold based derivatives were reported to display a wide range of biological activities including anticancer, anti-tubercular, antiviral, fungicidal, etc. On the other hand, 1,3,4-oxadiazoles were permit to increase their biological activities due to H-bonding with receptors. These derivatives possess diverse biological activities which include anticancer, antiviral, antifungal, antibacterial and antidepressant etc. Due to interesting biological activity information of about these hetero cyclic moieties, benzothiazole/2-aminobenzothiazole and 1,3,4-oxadiazoles moieties, we chose to design a new series of heterocyclic compounds by mimicking these two types of scaffolds in a single molecule for our study. Methods: The 1,3,4-oxadiazole linked benzothiazole derivatives were synthesized by condensation of, 2-(4-(5-(benzo[d]thiazol-2-yl)-1,3,4-thiadiazol-2-yl)-2,6-dimethoxyphenoxy)acetohydrazide and POCl3 under reflux conditions. All these ten compounds structures were confirmed by spectral data 1H & 13C NMR, Mass, CHN analysis etc. Further, these compounds were evaluated for their anticancer activity against four human cancer cell lines, A549, MCF7, A375 and HT-29 in comparison to CA4 as a reference drug. We also carried out docking studies of these compounds in the Colchicines binding site of Tubulin (PDB_ID: 1SA0) using Glide docking tool indicated that the ligands show good interactions with active site residues. Results: A new series of 1,3,4-oxadiazole fused benzothiazole derivatives were synthesized successfully in totally six steps starting with 4-hydroxy-3,5-dimethoxybenzoyl chloride. All these newly synthesized compounds structures were confirmed by spectral studies and elemental analysis. As we designed for anticancer activity, they were assessed for their anticancer activity against four human cancer cell lines in comparison to a reference drug CA4. As expected, all the ten compounds exhibited anticancer activities against four cancer cell lines with half maximal inhibitory concentration (IC50) values ranging from 0.01 μM to 12.3 μM. The docking studies indicated all the compounds exhibited good binding energies with the receptor. Conclusion: In this study we designed a new series heterocyclic compounds by mimicking two types of scaffolds benzothiazole/2-aminobenzothiazole and 1,3,4-oxadiazoles moieties in a single molecule based on their biological activity in the literature. They were synthesized successfully and molecular structures were confirmed by spectral studies. As expected, all the compounds exhibited anticancer activities against four cancer cell lines. This study can provide a roadmap for design and synthesis of new drug molecules for antitumor and anticancer activity.

Background: Magnetic targeting, which utilizes a magnetic field to specifically deliver therapeutic agents to the targeted regions, can greatly improve the treatment efficiency. On the other hand, glucose-modified nanoparticles have also demonstrated good brain-targeting abilities. Fusion of both might further improve the brain targeting efficiency. Objective: To prepare, characterize and evaluate glucose-modified ibuprofen-loaded brain targeting magnetic nanoparticles (MNPs-APS-Glu). Methods: The magnetic nanoparticles MNPs-APS-Glu were designed and synthesized in order to effectively deliver ibuprofen to the brain through glucose transporter 1 (GLUT1) and an external magnetic field. The nanoparticles were characterized by FTIR, SEM and magnetic properties, and the drug loading capacity, cell cytotoxicity and drug release behavior of the new magnetic nanoparticles was studied. Results: The size of MNPs-APS-Glu was about 104.9 nm, and its drug loading capacity was up to 5%. Furthermore, these brain targeting magnetic nanoparticles maintained the magnetic property with a saturation magnetization level at ca. 32 emu/g and could release ibuprofen when incubated with various buffers, mice plasma and brain homogenate. Conclusions: The results indicated that the magnetic nanoparticles had potential to be a promising tool to selectively deliver drugs to the brain. This study may be conducive to the field of Central Nervous System (CNS) drugs delivery.

Background: A series of new 6-(tert-butyl)-8-chloro-2,3-dimethyl quinoline derivatives were designed and synthesized. Results: The primarily antifungal assay results indicated that all of them exhibited excellent protective efficacy (100%) against Pyricularia oryae at 100 ppm, except compound 2m (90%). Among them, the compound 2p (6-(tert-butyl)-8-chloro-2,3-dimethylquinolin-4-yl(2-chloro-5- (trifluoromethyl)benzyl)carbonate) possessed the highest fungicidal efficacy against Pyricularia oryae, even at 10 ppm. Conclusion: The structure-activity relationship showed that when the 2-position of benzene ring was substituted by F or Cl, the compound possessed good antifungal activity against Pyricularia oryae.

Background: Bromodomain-containing protein 4 (BRD4) inhibitors synthesized with trimethoxy-ring refer to a new series of small molecular inhibitors. Currently, BRD4 offers the potential for research as a cancer therapeutic target. Based on previous studies, 17 trimethoxy-ring derivatives were designed as novel BRD4 inhibitors. Methods: All these new compounds were synthesized via the amide reaction. Their structures were identified by 1H NRM, 13C NRM spectra and HRMS. In vitro antitumor activities of the new compounds were evaluated by MTT. Molecular docking studies were conducted to explain the binding interactions of these compounds with BRD4 protein. Results: A series of novel trimethoxy-ring derivatives were synthesized as BRD4 inhibitors and screened by testing their inhibition against HCT116, MCF-7, K562 and KMS-1 cell lines. Most of the newly synthesized compounds exhibited moderate-to-good inhibitory activity against HCT116, MCF-7, and K562 cell lines, whereas some showed inhibitory activity against the KMS-1 cell line. Conclusion: Compound 3g demonstrated the most potent anti-tumor activity against breast (MCF-7), leukemia (K562), multiple myeloma (KMS-1), and colon cancer (HCT116) cell lines.

Background: Leishmaniasis is a neglected tropical disease, considered endemic in almost 98 countries worldwide, with 250 million new cases estimated annually. The usual drugs are considered toxic, expensive and frequently ineffective, justifying the search for new lead compounds. We presented here ligand-based classical QSAR study involving the leishmanicidal activity of quinoxaline derivatives and molecular descriptors of diverse nature, aimed to understand their molecular activities from a quantitative point of view. Additionally, the cytotoxic activity of the compounds was also modeled in a QSTR approach, in order to help the design of more active and safe leishmanicidal compounds. Methods: Geometry optimizations were performed by semiempirical and DFT quantum-chemical methods. Molecular descriptors were calculated by E-Dragon online platform and submitted to a variable selection procedure, using Ordered Predictors Selector algorithm. The best QSAR and QSTR models were selected by MLR modeling and structure-activity relationships were considered, in accordance to the successful of the validation parameters. Results: For leishmanicidal activity, five descriptors were selected as the most important, providing a robust and predictive QSAR model via Multiple Linear Regression (MLR) (R2 = 0.71, Qloo 2 = 0.60, Qext 2 = 0.76 and rtest = 0.87). On the other hand, cytotoxicity was better related to seven descriptors in QSTR approach (R2 = 0.77, Qloo 2 = 0.65, Qext 2 = 0.85 and rtest = 0.92). Analysis of descriptors influences on both activities revealed that there are common features that could be explored to provide a most leishmanicidal and less cytotoxic compound, at the same time, in order to design more active and safe compounds. Conclusion: In establishing of the structure-activity relationships and interpreting the physical sense of the descriptors, we can conclude that molecules containing sulfoxyl, sulfonyl and halogens tend to be most active, but molecules with large volumes and electronegative atoms tend to be less active. In addition, in a very interesting way, we could observe that small molecules containing sulfoxyl, sulfonyl and halogens tend to be less cytotoxic and larger molecules with fewer atoms of greater mass and electronegativity than carbon tend to be more cytotoxic. Fortunately, the combination of these characteristics can be explored in the synthesis and evaluation of new safe derivatives with better leishmanicidal profile.

Introduction: Oxadiazoles having azo-functionality represent a new and an exciting class of physiologically active heterocyclic compounds. A number of molecules with these moieties have significant role in medicinal chemistry due to their diverse biological activities. Methodology: A series of 1,3,4-oxadiazole-2-thiol derivatives bearing azo-moiety have been designed and synthesized by multistep reaction sequences staring from p-aminobenzoic acid by employing literature know procedures. These compounds were investigated for their antimicrobial, cytotoxic, α-amylase and protein kinase inhibitory and antileishmanial potential. Results and Discussion: The newly synthesized compounds were characterized by spectroscopic techniques (IR, UV-Vis, NMR and MS). Antibacterial activity was investigated against four bacterial strains i.e. E. coli, P. aeruginosa, S. aureusand B. subtilis and good level of microbial inhibition was exhibited by most of the compounds with MIC 6.25 μg/mL. Brine Shrimp lethality assay revealed that the compound 31 is an excellent cytotoxic agent. (E)-5-(4-((4-Butoxyphenyl) diazenyl)phenyl)-1, 3,4-oxadiazole-2-thiol (21) showed good α-amylase inhibition (46.3± 0.45%) and (E)-2-(Decyloxythio)-5-(4-((propoxyphenyl)diazenyl)phenyl)-1,3,4-oxadiazole (30) exhibited excellent antileishmanial activity (88.4± 0.34%) at 10 μg/mL concentration. In case of protein kinase inhibition, remarkably, the oxadiazole-2-thiols (20-25) were found more active than the standard surfactinat tested concentration (25 μg/disc). Conclusion: We have designed, synthesized and characterized an interesting series of biologically active oxadiazole bearing diazene moiety derivatives. Noteworthy, the presence of diazene functionality, polar heterocyclic moiety as well as hydrophobic alkyl chain is special feature of these compounds. These studies provide a basic idea to further explore these types of scaffolds as biologically potent molecules in drug design and development.