Medicinal Chemistry Research

Preparation and biological evaluation of quinoline amines as anticancer agents and its molecular docking Abstract A series of 2-chloro N-substituted amino quinolines (2a–2j) were prepared and characterized by analytical and spectroscopic methods. As quinoline is an important pharmacophoric moiety, the prepared compounds were screened against a non-small cell lung cancer cell line, A549. One of the compounds, 2-chloro-8-methyl-N-(quinolin-5-yl)quinolin-4-amine (2b) is found to be active with inhibition concentration value of (IC50) 29.4 μM. The molecular docking studies with the predominant PI3K/AKT/mTOR pathway proteins also revealed the lesser binding energy with 2b. All the compounds are predicted to satisfy the ADME profile and the results let us to consider 2b as a lead compound for new generation of A549 cell line inhibitors and for further studies in this way.

Green synthesis and 3D pharmacophore study of pyrimidine and glucoside derivatives with in vitro potential anticancer and antioxidant activities Abstract A facile and an efficient one-pot green synthesis of pyrimidine derivatives using the environmentally friendly Cerium(IV) ammonium nitrate (CAN) as catalyst and water as a solvent has been described. Some of the synthesized pyrimidines react with 2,3,4,6-tetra-O-acetyl-α-d-glucopyranosyl bromide in ethanol containing potassium hydroxide to give S-glucoside derivatives. The structures of the newly synthesized compounds were elucidated on the basis of their spectral and elemental analyses. In addition, selected derivatives of the products were screened for their anticancer activities against four tumor cell lines using MTT assay and the results showed that some of these compounds have potent cytotoxic effect, as concluded from their IC50 values. Molecular modeling studies including generation of a 3D pharmacophore model were carried out. The study showed high correlation with the experimental results. Antioxidant activity of the synthesized products was also investigated and most of them showed potent activity.

In vitro activity of novel derivatives of 1,3-oxazole-4-carboxylate and 1,3-oxazole-4-carbonitrile against human cytomegalovirus Abstract Ten 5-functionalized derivatives of 1,3-oxazole-4-carboxylate and 1,3-oxazole-4-carbonitrile were synthesized and their antiviral activities against the human cytomegalovirus (HCMV) were evaluated in vitro. Bioassays showed that seven compounds exhibited considerably higher antiviral activity (EC50: < 0.05 μM) against a normal laboratory HCMV strain (AD-169) in human foreskin fibroblast cells than Ganciclovir (EC50 = 0.32 μM), an anti-HCMV agent in clinical use. Additionally, the HCMV-resistant isolate (GDGr K17) was tested for sensitivity to 1,3-oxazole derivatives with most antiviral potency against the strain AD169. A one of them (5-((2-hydroxyethyl)(methyl)amino)-2-(4-methylphenyl)-1,3-oxazole-4-carbonitrile) showed very high potency (EC50: < 0.05; CC50: >150 µM, and SI50 = 3125) towards the resistant isolate compared to standard drugs Cidofovir (EC50 = 0.10 µM, CC50: >30 µM and SI50: <4). But, in contrast to the primary assays, the antiviral activity of these compounds against both the normal strain and the resistant isolate of HCMV were considerably less than one of Cidofovir in secondary assay. These results provided evidence that derivatives of 1,3-oxazole could be useful for developing new anti-HCMV drugs.

New fluoroquinolones/nitric oxide donor hybrids: design, synthesis and antitubercular activity Abstract New nitric oxide (NO) donating fluoroquinolones/nitrate ester hybrids were prepared and their structures were characterized by various spectroscopic and analytical tools. The release of NO from the prepared nitrate esters was measured using the modified Griess colorimetric method. Evaluation of antitubercular activity showed that most of tested compounds exhibited comparable or higher activity than the parent fluoroquinolones. Compounds 2b, 3a, 4a, 5a, and 2d showed better activity than ciprofloxacin. Nevertheless, none of the new compounds were superior to the parent fluoroquinolones in terms of DNA cleavage stimulation in mycobacteria. The additional growth inhibition effect that is distinct from gyrase poisoning may be due to release of NO or enhancement of lipophilicity. These data are augmented by docking results where the docked compounds did not exert additional significant bindings over the parent fluoroquinolones.

3D-QSAR, molecular docking, and new compound design of pyrimidine derivatives as Src small molecule inhibitors Abstract Non-receptor tyromethod, The sine kinase Src is one of the important molecular targets for potential triple-negative breast cancer (TNBC). In this study, the structure and acitivity relationship of 51 Src small molecule inhibitors with potential pyrimidine derivatives was explored. On the basis of ligand composite, the relationsConducted a phase hip between molecular structure and inhibitory activity of MDA-MB-231/435 TNBC cell lines was studied by using comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis fields (CoMSIA), and Topomer CoMFA (T-COMFA) methods, and thereby two sets of three-dimensional quantitative structure–activity relationship models were established to analyze the molecular structure and anti-TNBC activity. The results indicated that the q2 of CoMFA, CoMSIA, and Topomer CoMFA models was 0.698/0.719, 0.73/0.684, 0.674/0.683, and r2 was 0.994/0.991, 0.991/0.985, 0.946/0.959, respectively. Moreover, the three-dimensional equipotential map also revealed the relationship between structural characteristics and inhibitory activity, and molecular docking was investigated by Surflex-dock. The data proved that this model had good predictive ability and can further guide the design and modification of 3- (phenylethynyl) −1 hydropyrazolyl [3anilo-d] pyrimidine-4-amine derivatives inhibitors. According to the three-dimensional quantitative structure–activity relationship model of two TNBC cell lines of MDA-MB-231/435, 13 and 11 compounds were designed respectively, and the predicted activity values showed effective inhibition of SRC.

Synthesis and in vitro evaluation of substituted tetrahydroquinoline-isoxazole hybrids as anticancer agents Abstract A series of isoxazole linked to 4-(2-oxopyrrolinidyl-1)-tetrahydroquinoline derivatives was efficiently synthesized. The synthetic route started with the formation of the corresponding N-propargyl tetrahydroquinoline derivatives via cationic Povarov reaction. Tetrahydroquinoline-isoxazole hybrid systems (3a–p) were obtained with good yields (42–88%) through a 1,3-dipolar cycloaddition reaction with a click chemistry approach. These compounds have been tested for their in vitro cytotoxic activity against four different human cancer cell lines, lung (A549), liver (HepG2), and melanoma murine (B16F10) using the conventional MTT assay. Among all tetrahydroquinoline-isoxazole hybrids synthesized, compounds 3a, 3e, 3j, and 3m showed promising in vitro activity against HepG2 cancer cell line with considerable selectivity. Compounds 3a (IC50 = 6.80 µM, SI = 14.7) and 3j (IC50 = 5.20 µM, SI > 16.1) exhibited the highest cytotoxic effect. The death pathway related to cytotoxicity of the compound 3j showed necrotic characteristics selectively on the tumor cell line, also showed an improved in vitro activity against the tested reference drug (oxaliplatin), without significant affectation on the viability of hepatocytes. In general, results suggested that these type of hybrid compounds might have therapeutic potential in future investigations on hepatocellular carcinoma.

Pyrazole–chalcone derivatives as selective COX-2 inhibitors: design, virtual screening, and in vitro analysis Abstract In the process of research and development of new drugs, in silico analyzes are widely used. They address the pharmacokinetics of the molecules in study and can predict the binding mode and affinity, using a docking software. This approach can optimize the development of new drugs, reducing costs, time, and resources. In this study, a library of 300 pyrazole–chalcone derivatives were designed, the in silico ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties were evaluated, and a structure-based virtual screening was performed using AutoDock Vina. The docking results exhibited that the derivatives binding mode at the COX-2 active site is similar to celecoxib, the reference drug, and presented similar binding energy. Six compounds were synthetized and tested for in vitro inhibition of the COX-1 and COX-2 isoenzymes and the selectivity index (SI) was calculated. The compound 2a11 showed the best activity for COX-2 (IC50COX-2 = 0.73 μM) whereas the control, celecoxib, resulted IC50COX-2 = 0.88 μM. All the other compounds synthetized presented better potency for COX-2 inhibition than the control. Compound 2a23 exhibited the higher SI, of 280.17 (IC50COX-1 = 210.13 μM/ IC50COX-2 = 0.75 μM), while celecoxib was 246.88 (IC50COX-1 = 217.26 μM/ IC50COX-2 = 0.88 μM). These results corroborate with a possible anti-inflammatory activity and COX-2 selectivity of the new compounds synthetized.

Natural thiopeptides as a privileged scaffold for drug discovery and therapeutic development Abstract Since the start of the 21st century, antibiotic drug discovery and development from natural products has experienced a certain renaissance. Currently, basic scientific research in chemistry and biology of natural products has finally borne fruit for natural product-derived antibiotics drug discovery. A batch of new antibiotic scaffolds were approved for commercial use, including oxazolidinones (linezolid, 2000), lipopeptides (daptomycin, 2003), and mutilins (retapamulin, 2007). Here, we reviewed the thiazolyl peptides (thiopeptides), an ever-expanding family of antibiotics produced by Gram-positive bacteria that have attracted the interest of many research groups thanks to their novel chemical structures and outstanding biological profiles. All members of this family of natural products share their central azole substituted nitrogen-containing six-membered ring and are classified into different series. Most of the thiopeptides show nanomolar potencies for a variety of Gram-positive bacterial strains, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and penicillin-resistant Streptococcus pneumonia (PRSP). They also show other interesting properties such as antiplasmodial and anticancer activities. The chemistry and biology of thiopeptides has gathered the attention of many research groups, who have carried out many efforts towards the study of their structure, biological function, and biosynthetic origin. Here we reviewed a total of 119 natural thiopeptides discovered during the last 50 years. Moreover, we summarized biological profiles, mechanisms of action, and biosynthesis of these thiopeptides.

A structure–activity relationship study of phenyl sesquiterpenoids on efflux inhibition against Staphylococcus aureus Abstract Sixteen natural acetophenone sesquiterpene derivatives were isolated from Ferula ferulioides and 11 synthetic acetophenone sesquiterpene analogues were evaluated to explore the structure–activity relationships (SARs) on their antibacterial activities against a panel of bacteria including drug-resistant Staphylococcus aureus. The minimum inhibitory concentration (MIC) values of the compounds were in the range of 0.5–128 mg/L. Preliminary SAR studies showed that subtle modifications on both the 2',4'-dihydroxyphenyl moiety and the side chain reduced their activity against drug-resistant S. aureus. All of the compounds that showed no or only weak direct antibacterial activity were tested for their efflux inhibitory effects, among which four compounds showed significant efflux inhibition against drug-resistant strains. Natural product 14 showed significant inhibitory effects for EtBr efflux in strain SA1199B, which has reduced susceptibility to fluoroquinolones by efflux. Compounds 5, 14 and F-3 moderately inhibited EtBr efflux in the macrolide-resistant strain RN4220 and compound 13moderately inhibited efflux in an MRSA and effluxing tetracycline-resistant strain.

Synthesis of oleanolic acid/ursolic acid/glycyrrhetinic acid-hydrogen sulfide donor hybrids and their antitumor activity Abstract A total of 25 targeted hydrogen sulfide donor–pentacyclic triterpene hybrids were designed, synthesized and evaluated on the basis of inspiring reports about hydrogen sulfide donor molecules and oleanolic acid derivatives on anti-tumor activity. The results revealed that only some hybrids (10a, 10b, 12a, 12b, 13a, and 15b) showed moderate anti-proliferation activity against K562 cell line. It indicated that oleanane-type, (R)-lipoic acid and TBZ groups were much more favorable to the anti-proliferation activity. Furthermore, C-3 OH was more beneficial than C-28/29 COOH in the oleanane-type to the antitumor activity of the batch of (R)-lipoic acid derivatives. And among them, only compound 13a exhibited moderate anti-proliferation activity against both K562 and K562/ADR cell lines, while it exhibited no anti-proliferation activity against BEL-7402 and L-O2 cell lines. Therefore, it suggested that it was not suitable for hybridization of hydrogen sulfide donors attached to oleanolic acid, ursolic acid and glycyrrhetinic acid in the field of anti-tumor.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com