Design,synthesis and evaluation of novel hybrids between 4-anilinoquinazolines and substituted triazoles as potent cytotoxic agents

In this research several series of novel dioxygenated ring fused 4-anilinoquinazolines (10a-d) and 4-anilinoquinazoline-substituted triazole hybrid compounds (11–14) have been designed and synthesized. Their biological significance was highlighted by evaluating in vitro for anticancer activities, wherein several compounds displayed excellent activity specifically against three human cancer cell lines (KB, epidermoid carcinoma; HepG2, hepatoma carcinoma; SK-Lu-1, non-small lung cancer). Especially, compound 13a exhibited up to 100-fold higher cytotoxicity in comparison with erlotinib. Docking the most cytotoxic compounds (11d, 13a, 13b, and 14c) into the ATP binding site of different EGFR tyrosine kinase domains was perfomed to predict the analogous binding mode of these compounds to the EGFR targets.     

Design and optimization of potent, selective antagonists of Oxytocin

A novel series of Oxytocin antagonists are described. This series was identified through pharmacophoric overlap of in-house and literature antagonists. Subsequent optimization led to a series of potent, selective antagonists. Several analogues displayed oral bioavailability in vivo in the rat.     

Design,synthesis, and in vitro evaluation of novel antifungal triazoles

Twenty-nine novel triazole analogues of ravuconazole and isavuconazole were designed and synthesized. Most of the compounds exhibited potent in vitro antifungal activities against 8 fungal isolates. Especially, compounds a10, a13, and a14 exhibited superior or comparable antifungal activity to ravuconazole against all the tested fungi. Structure-activity relationship study indicated that replacing 4-cyanophenylthioazole moiety of ravuconazole with fluorophenylisoxazole resulted in novel antifungal triazoles with more effectiveness and a broader-spectrum.     

Design and synthesis of potent, highly selective vasopressin hypotensive agonists.

We report here the solid-phase synthesis and vasodepressor potencies of a new lead vasopressin (VP) hypotensive peptide [1(beta-mercapto-beta,beta-pentamethylenepropionic acid)-2-0-ethyl-D-tyrosine, 3-arginine, 4-valine, 7-lysine, 9-ethylenediamine] lysine vasopressin, d(CH(2))(5)[D-Tyr(Et)(2), Arg(3), Val(4), Lys(7), Eda(9)]LVP (C) and 21 analogues of C with single modifications at positions 9 (1-13), 6 (14), 2 (16-20) and combined modifications at positions 6 and 10 (15) and 2 and 10 (21). Peptides 1-13 have the following replacements for the Eda residue at position 9 in C: (1) Gly-NH(2); (2) Gly-NH-CH(3); (3) Ala-NH(2); (4) Ala-NH-CH(3), (5) Val-NH(2); (6) Cha-NH(2); (7) Thr-NH(2); (8) Phe-NH(2); (9) Tyr-NH(2); (10) Orn-NH(2); (11) Lys-NH(2); (12) D-Lys-NH(2); (13) Arg-NH(2). Peptide 14 has the Cys residue at position 6 replaced by Pen. Peptide 15 is the retro-Tyr(10) analogue of peptide 14. Peptides 16-20 have the D-Tyr(Et) residue at position 2 in C replaced by the following substituents: D-Trp (16); D-2-Nal (17); D-Tyr(Bu(t))(18); D-Tyr(Pr(n)) (19); D-Tyr(Pr(i)) (20). Peptide 21 is the retro-Tyr(10) analogue of peptide 20. C and peptides 1-21 were evaluated for agonistic and antagonistic activities in in vivo vasopressor (V(1a)-receptor), antidiuretic (V(2)-receptor), and in in vitro (no Mg(2+)) oxytocic (OT-receptor) assays in the rat, and, like the original hypotensive peptide, d(CH(2))(5)[D-Tyr(Et)(2), Arg(3), Val(4)]AVP (A) (Manning et al., J. Peptide Science 1999, 5:472-490), were found to exhibit no or negligible activities in these assays. Vasodepressor potencies were determined in anesthetized male rats with baseline mean arterial blood pressure (BP) maintained at 100-120 mmHg. The effective dose (ED), in microg/100 g i.v., the dose required to produce a vasodepressor response of 5 cm(2) area under the vasodepressor response curve (AUC) during the 5-min period following the injection of the test peptide, was determined. The EDs measure the vasodepressor potencies of the hypotensive peptides C and 1-21 relative to that of A (ED = 4.66 microg/100 g) and to each other. The following ED values in microg/100 g were obtained for C and for peptides 1-21; C 0.53; (1) 2.41; (2) 1.13; (3) 1.62; (4) 0.80; (5) 1.83; (6) 1.56; (7) 2.12, (8) 2.58; (9) 1.40; (10) 0.88; (11) 0.90; (12) 0.85; (13) 0.68; (14) 0.99; (15) 1.05; (16) 0.66; (17) 0.54; (18) 0.33; (19) 0.18; (20) 0.15; (21) 0.14. All of the hypotensive peptides reported here are more potent than A. Peptides 20 and 21 exhibit a striking 30-fold enhancement in vasodepressor potencies relative to A. With a vasodepressor ED = 0.14, peptide 21 is the most potent VP vasodepressor agonist reported to date. Because it contains a retro-Tyr(10) residue, it is a promising new radioiodinatable ligand for the putative VP vasodilating receptor. Some of these new hypotensive peptides may be of value as research tools for studies on the complex cardiovascular actions of VP and may lead to the development of a new class of antihypertensive agents.     

Design,synthesis, and cytotoxic activities of isaindigotone derivatives as potential anti-gastric cancer agents

A series of novel derivatives of isaindigotone, which comes from the root of isaits indinatca Fort, were synthesised (Compound 1–26). Four human gastrointestinal cancer cells (HCT116, PANC-1, SMMC-7721, and AGS) were employed to evaluate the anti-proliferative activity. Among them, Compound 6 displayed the most effective inhibitory activity on AGS cells with an IC₅₀ (50% inhibitory concentration) value of 2.2 μM. The potential mechanism study suggested that Compound 6 induced apoptosis in AGS cells. The collapse of mitochondrial membrane potential (MMP) in AGS cells was proved. In docking analysis, good affinity interaction between Compound 6 and AKT1 was discovered. Treatment of AGS cells with Compound 6 also resulted in significant suppression of PI3K/AKT/mTOR signal pathway. The collapse of MMP and suppression of PI3K/AKT/mTOR signal pathway may be responsible for induction of apoptosis. This derivative Compound 6 could be useful as an underlying anti-tumour agent for treatment of gastric cancer.     

Design,synthesis and biological evaluation of new potent and highly selective ROS1-tyrosine kinase inhibitor

ROS1 protein is a receptor tyrosine kinase that has been reported mainly in meningiomas and astrocytomas, and until now, there is no selective inhibitor for this kinase. In this study, we illustrate for the synthesis of a highly potent and selective inhibitor for ROS1 kinase. The synthesized compound 1 was tested initially at a single dose concentration of 10 μM over 45 different kinases. At this concentration, a 94% inhibition of the enzymatic activity of ROS1 kinase was observed, while the inhibition in activity was below 30% in all of the other kinases. The pyrazole compound 1 was further tested in a 10-dose IC₅₀ mode and showed an IC₅₀ value of 199 nM for ROS1 kinase. The compound 1 can be used as a promising lead for the development of new selective inhibitors for ROS1 kinase, and it may open the way for new selective therapeutics for astrocytomas.     

Synthesis and biological evaluation of novel isoxazoles and triazoles linked 6-hydroxycoumarin as potent cytotoxic agents

A new series of diverse isoxazoles and triazoles linked 6-hydroxycoumarin (1) were synthesized using click chemistry approach. All the derivatives were subjected to 3-(4,5-dimethylthiazol-yl)-diphenyl tetrazoliumbromide (MTT) cytotoxicity screening against a panel of five different human cancer cell lines viz. prostate (PC-3), colon (HCT-116 and Colo-205), leukemia (HL-60) and lung (A-549) to check their cytotoxic potential. Interestingly, among the tested molecules, some of the analogs displayed better cytotoxic activity than the parent 6-hydroxycoumarin (1). Of the synthesized isoxazoles, compounds 10 and 13 showed the best activity with IC₅₀ of 8.2 and 13.6 μM against PC-3 cancer cell line, while as, among the triazoles, compounds 23 and 25 were the most active with the IC₅₀ of 10.2 and 12.6 μM against A-549 cancer cell line. The other derivatives showed almost comparable activity with that of the parent molecule. The present study resulted in identification of ortho substituted isoxazole and triazole derivatives of 6-hydroxycoumarin as effective cytotoxic agents against prostate (PC-3) and lung (A-549) cancer cell lines, respectively.     

Design and synthesis of highly potent and selective human peroxisome proliferator-activated receptor alpha agonists

A combination of benzoxazole, phenoxyalkyl side chain, and phenoxybutyric acids was identified as a highly potent and selective human peroxisome proliferator-activated receptor alpha (PPARalpha) agonist. The synthesis, structure-activity relationship (SAR) studies, and in vivo activities of the representative compounds are described.     

Design and synthesis of highly potent and selective melanotropin analogues of SHU9119 modified at position 6

The melanocortin receptors are involved in several important physiological functions. The potent and enzymatically stable analogues MT-II (Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH(2)) and SHU9119 (Ac-Nle-c[Asp-His-DNal(2')-Arg-Trp-Lys]-NH(2)) are important ligands of these receptors but are relatively nonselective. To differentiate between the physiological functions of these receptors, agonists, and antagonists with improved receptor selectivities are needed. We report here analogues of the well-characterized antagonist SHU9119 in which we replaced His(6) with conformationally constrained amino acids. By this structure-activity study we discovered two important compounds, PG-901 (Ac-Nle(4)-c[Asp(5)-Pro(6)-DNal(2')(7)-Arg(8)-Trp(9)-Lys(10)]-NH(2)) and PG-911 (Ac-Nle(4)-c[Asp(5)-Hyp(6)-DNal(2')(7)-Arg(8)-Trp(9)-Lys(10)]-NH(2)), characterized to be full agonists at the hMC5R (EC(50) = 0.072 nM and 0.031 nM, respectively), but full antagonists at the hMC3R and the hMC4R. We also demonstrated that the relative stereochemistry of the amino acid at the 6-position is critical for activity, and could play an important role in potency as well as in selectivity for the melanocortin receptors.     

Design and one-pot synthesis of new 7-acyl camptothecin derivatives as potent cytotoxic agents

New 7-acyl camptothecin derivatives were designed and synthesized from camptothecin in a one-pot reaction through a Minisci type-reaction and were evaluated for cytotoxicity against four tumor cell lines, A-549, DU-145, KB, and KB-vin. All of the new compounds showed significant inhibition of human tumor cell growth, with IC₅₀ values ranging from 0.01538 to 13.342 μM. Most of the derivatives were more cytotoxic than irinotecan, and the (7a) and 7-propionyl (7b) analogs exhibited the highest cytotoxic activity against the tumor cell lines tested. This compound class merits further development as anticancer clinical trial candidates.     

Discovery of novel bis-oxazolidinone compounds as potential potent and selective antitubercular agents

A variety of new mono-oxazolidinone molecules by modifying the C-ring of Linezolid, a marketed antibiotic for MRSA, were synthesized and tested for their in vitro antibacterial activities against several Staphylococcus aureus, Mycobacterium smegmatis and two Gram-negative bacteria strains (Escherichia coli and Pseudomonas aeruginosa). Among them, compounds 4–7 displayed moderate antimicrobial activities. After development of a second oxazolidinone ring in the western part of the mono-oxazolidinone compounds 4–7 by a ring closure reaction with N,N′-carbonyldiimidazole (CDI), we found thus obtained bis-oxazolidinone compounds 22–25 possess excellently inhibitory activities against H₃₇Rv but poor or no effects on other test bacteria. Among them, bis-oxazolidinone compound 22 and 24 are the most potent two compounds with a same MIC value of 0.125 μg/mL against H₃₇Rv virulent strain. Compound 22 also exhibited extremely low cytotoxicity on monkey kidney Vero cells with a selective index (IC₅₀/MIC) over 40,000, which suggested bis-oxazolidinone compound 22 is a promising lead compound for subsequent investigation in search of new antitubercular agents.     

Design and synthesis of potent and selective macrocyclic thrombin inhibitors

A series of potent and selective proline- and pyrazinone-based macrocyclic thrombin inhibitors is described. Detailed SAR studies led to the incorporation of specific functional groups in the tether that enhanced functional activity against thrombin and provided exquisite selectivity against trypsin and tPA. X-ray crystallography and molecular modeling studies revealed the inhibitor-enzyme interactions responsible for this selectivity.     

The discovery and synthesis of highly potent subtype selective phosphodiesterase 4D inhibitors

The SAR study of a series of 6-aryloxymethyl-8-aryl substituted quinolines is described. Optimization of the series led to the discovery of compound 26b, a highly potent (IC₅₀ = 0.6 nM) and selective PDE4D inhibitor with a 75-fold selectivity over the A, B, and C subtypes and over 18,000-fold selectivity against other PDE family members. Rat pharmacokinetics and tissue distribution are also summarized.     

Synthesis and biological evaluation of a class of quinolone triazoles as potential antimicrobial agents and their interactions with calf thymus DNA

A novel series of quinolone triazoles were synthesized and characterized by IR, NMR, MS and HRMS spectra. All the newly prepared compounds were screened for their antimicrobial activities against seven bacteria and four fungi. Bioactive assay manifested that most of new compounds exhibited good or even stronger antibacterial and antifungal activities against the tested strains including multi-drug resistant MRSA in comparison with reference drugs Norfloxacin, Chloromycin and Fluconazole. The preliminary interactive investigations of compound 6b with calf thymus DNA by fluorescence and UV–vis spectroscopic methods revealed that compound 6b could effectively intercalate DNA to form compound 6b–DNA complex which might block DNA replication and thus exert its antimicrobial activities.     

Design and synthesis of amidoxime derivatives for orally potent C-alkylamidine-based antimalarial agents

Within the frame of the design of prodrug candidates to deliver a C-alkylamidine antimalarial agent, we showed that specific O-substitutions were needed on the alkylamidoxime structure. Among the newly synthesized molecules, bis-oxadiazolone and bis-O-methylsulfonylamidoxime derivatives induced a complete clearance of parasitemia in mice after oral administration.     

Design and synthesis of a potent,highly selective,orally bioavailable,retinoic acid receptor alpha agonist

A ligand-based virtual screening exercise examining likely bioactive conformations of AM 580 (2) and AGN 193836 (3) was used to identify the novel, less lipophilic RARα agonist 4-(3,5-dichloro-4-ethoxybenzamido)benzoic acid 5, which has good selectivity over the RARβ, and RARγ receptors. Analysis of the medicinal chemistry parameters of the 3,5-substituents of derivatives of template 5 enabled us to design a class of drug-like molecules with lower intrinsic clearance and higher oral bioavailability which led to the novel RARα agonist 4-(3-chloro-4-ethoxy-5-isopropoxybenzamido)-2-methylbenzoic acid 56 that has high RARα potency and excellent selectivity versus RARβ (2 orders of magnitude) and RARγ (4 orders of magnitude) at both the human and mouse RAR receptors with improved drug-like properties. This RARα specific agonist 56 has high oral bioavailability (>80%) in both mice and dogs with a good PK profile and was shown to be inactive in cytotoxicity and genotoxicity screens.     

Development of highly potent and selective dynorphin A analogues as new medicines.

Dynorphin A (Dyn A), a 17 amino acid peptide H-Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asn-Gln-OH, is a potent opioid peptide which interacts preferentially with kappa-opioid receptors. Research in the development of selective and potent opioid peptide ligands for the kappa-receptor is important in mediating analgesia. Several cyclic disulphide bridge-containing peptide analogues of Dyn A, which were conformationally constrained in the putative message or address segment of the opioid ligand, were designed, synthesized and assayed. To further investigate the conformational and topographical requirements for the residues in positions 5 and 11 of these analogues, a systematic series of Dyn A(1-11)-NH2 cyclic analogues incorporating the sulphydryl-containing amino acids L- and D-Cys and L- and D-Pen in positions 5 and 11 were synthesized and assayed. Cyclic lactam peptide analogues were also synthesized and assayed. Several of these cyclic analogues, retained the same affinity and selectivity (vs. the mu- and delta-receptors) as the parent Dyn A(1-11)-NH2 peptide in the guinea-pig brain (GPB), but exhibited a much lower activity in the guinea-pig ileum (GPI), thus leading to centrally vs. peripherally selective peptides. Studies of the structure-activity relationship of Dyn A peptide provide new insights into the importance of each amino acid residue (and their configurations) in Dyn A analogues for high potency and good selectivity at kappa-opioid receptors. We report herein the progress towards the development of Dyn A peptide ligands, which can act as agonists or antagonists at cell surface receptors that modulate cell function and animal behaviour using various approaches to rational peptide ligand-based drug design.     

Design and synthesis of new 7-(N-substituted-methyl)-camptothecin derivatives as potent cytotoxic agents

A series of novel 7-(N-substituted-methyl)-camptothecin derivatives was designed, synthesized, and evaluated for in vitro cytotoxicity against four human tumor cell lines, A-549, MDA-MB-231, KB, and KBvin. All of the derivatives showed promising in vitro cytotoxic activity against the tested tumor cell lines, with IC₅₀ values ranging from 0.0023 to 1.11 μM, and were as or more potent than topotecan. Compounds 9d, 9e, and 9r exhibited the highest antiproliferative activity among all prepared derivatives. Furthermore, all of the compounds were more potent than paclitaxel against the multidrug-resistant (MDR) KBvin subline. With a concise efficient synthesis and potent cytotoxic profiles, especially significant activity towards KBvin, compounds 9d, 9e, and 9r merit further development as a new generation of camptothecin-derived anticancer clinical trial candidates.     

Design and synthesis of 1,3-biarylsulfanyl derivatives as new anti-breast cancer agents

A new series of 1,3-biarylsulfanyl derivatives (homodibenzyl core motif) have been designed and synthesized as new estrogen receptor ligands by chopping benzothiophene core of raloxifene to engender seco-raloxifene scaffold. All the synthesized compounds were screened for anti-proliferative, anti-osteoporotic, and anti-implantation activity. Compounds (35, 36) having basic amino anti-estrogenic side chain were exhibiting potential anti-proliferative activity in MCF-7, MDA-MB-231 and ishikawa cell lines. Some of the synthesized compounds having homodibenzyl motif (5, 8, 10) have shown moderate anti-osteoporotic activity.     

Design and multi-step synthesis of chalcone-polyamine conjugates as potent antiproliferative agents

The aim of this study is to synthesize chalcone-polyamine conjugates in order to enhance bioavailability and selectivity of chalcone core towards cancer cells, using polyamine-based vectors. 3-hydroxy-3′,4,4′,5′-tetramethoxychalcone (1) and 3′,4,4′,5′-tetramethoxychalcone (2) were selected as parent chalcones since they were found to be efficient anti-proliferative agents on various cancer cells. A series of ten chalcone-polyamine conjugates was obtained by reacting carboxychalcones with different polyamine tails. Chalcones 1 and 2 showed a strong cytotoxic activity against two prostatic cancer (PC-3 and DU-145) and two colorectal cancer (HT-29 and HCT-116) cell lines. Then, chalcone-spermine conjugates 7d and 8d were shown to be the most active of the series and could be considered as promising compounds for colon and prostatic cancer adjuvant therapy.