Letters in Drug Design & Discovery - Volume 12, Issue 10, 2015

In this study, we tried to improve the anticancer properties of two potential cytostatic agents based on benzo[c]fluorene, benfluron and dimefluron, by the synthesis of their C-7 derivatives. In the new derivatives, we observed the effect in Ehrlich tumour-bearing mice as well as in human MCF-7, BT-549 and MDA-MB-231 cells. All of the compounds tested showed a strong inhibitory effect in vitro. When tested in vivo, their systemic toxicity in vivo was promisingly low. Benfluron and its O-methyloxime as well as dimefluron and its oxime, thiosemicarbazone and hydrazone inhibited tumour growth in vivo. Only benfluron and hydrazone of dimefluron prolonged the survival. Proliferating cell nuclear antigen (PCNA) protein was decreased in tumours treated with benfluron and O-methyloxime of dimefluron in cancer tissue. Benfluron thiosemicarbazone increased the infiltration of tumour with T-lymphocytes. Taken together, all derivatives were more cytotoxic then their parent compounds, but not necessarily more effective in vivo.

A series of simple isatin Schiff bases were synthesized through the condensation reaction. These isatin Schiff bases were characterized by NMR and MS, and the structure was discussed. Then, the cytoprotective and anti-tumor activities of these compounds were evaluated. The results show that several compounds show protection activity on the apoptosis of PC12 cells induced by H2O2, which are more effective than that of (±) α-Tocophreol (VE) and isatin. Besides, some compounds also show more potent anti-tumor activity against A549 and P388 cell lines than that of isatin.

Chalcones and Mannich bases are bioactive compounds and known with their cytotoxicities. α,β-Unsaturated ketones are reported with their alkylating potential to cellular thiols thereby inducing cytotoxicities. In this study; Mannich bases (MT2-MT7), which may generate two additional alkylating centers comparing with starting compound 2-(4-hydroxybenzylidene)-2,3-dihydroinden-1- one MT1, were designed and synthesized expecting the increased cytotoxicities in bis Mannich bases. Their cytotoxicities were tested against Ca9-22, HSC-2, HSC-3, and HSC-4 human oral squamous cell carcinoma as tumour cell lines and HGF, HPC, and HPLF human normal oral cells as non tumour cell lines. Amine parts were changed as N-methylpiperazine (MT2), pyrrolidine (MT3), morpholine (MT4), piperidine (MT5), dimethylamine (MT6), and dipropylamine (MT7). As conclusion, Mannich bases prepared showed higher cytotoxicity and slightly reduced tumor-specificity than starting compound MT1. The results of stability studies with MT1, which is a chalcone analogue, and MT2, which is a Mannich base, suggested that the mechanism of action for the cytotoxicities of the compounds can be different from thiol alkylation in contrast to our expectation since it was not obtained any thiol adduct by stability study. However, the Mannich bases MT3, MT5, MT6, and MT7 showed tumour selectivity (TS) values higher than 1 and this suggests that they can be candidate compounds for further studies.

In this work, a series of N-substituted isatin derivatives was synthesized by different reactions. The synthesized isatin derivatives were characterized by NMR, MS and elemental analysis. Then the anti-tumor activities of these compounds were evaluated through the cytotoxicity against A549 and P388 cell line test. The results show that several compounds show much higher anti-tumor activity than that of isatin, and there is an even-odd effect in the structure activity relationship.

Identification of compounds which can inhibit the activity of urease enzyme is an important approach towards the treatments of peptic ulcer, urolithiasis, and other urease associated disorders. This manuscript describes the in vitro urease inhibitory activity of different derivatives of phenols, heterocyclic compounds, thiols, quinone, tosylphenyl alanine, sulfonyl cyanides, phenyl acetoacetate, and thiamines (1-14). Among them, compound 10 was found to be more active with IC50 of 12.40 ± 1.57 µM, in comparison to the standard drug, acetohydroxamic acid (IC50= 41.5 ± 1.50 µM). Compounds 8 (IC50 = 21.0 ± 1.16 µM), and 9 (IC50= 24.94 ± 1.13 µM), were also identified as potent inhibitors of urease enzyme. All active compounds were largely found to be non-cytotoxic against fibroblast cell line (3T3 cell line). All potent compounds were also subjected to the mechanistic studies, as well as ligand-binding study by employing STD-NMR spectroscopy. In brief, this mechanism- based study identifies potent inhibitors of urease enzyme in vitro, as leads for further studies.

The pseudo-trisaccharide allosamidin 1 is a potent inhibitor of all family 18 chitinases, and it is confirmed to have insecticidal and antifungal activities. However, the synthesis of allosamidins is very difficult, and it is a challengeable subject. Allosamidins were synthesized in solid/liquid phase and total solid phase, respectively. Solid/liquid-phase method realizes the partial solid-phase synthesis of allosamidins. Total solid-phase method greatly simplifies the purification process. Moreover, it indicated that the inhibitory activity of N,N'-diacetyl-β-chitobiosylallosamizoline 9 against chitinase from Bombyx mori was a little weaker than that of allosamidin 1.

The brain serotonin (5-HT) and dopamine (DA) systems are targets for many clinically effective antidepressants. Here, we studied the effects of acute administration of a new potential antidepressant drug, 8-(trifluoromethyl)-1,2,3,4,5 - benzopentathiepin-6-amine hydrochloride (TC-2153), on the concentration of 5-HT and DA as well as their main metabolites, 5-hydroxyindoleacetic (5-HIAA) and homovanillic acids (HVA), in the brain. TC-2153 at the doses of 10, 20 or 40 mg/kg was administered by ip injection to adult C57BL/6 mouse males. The levels of 5-HT, 5-HIAA, DA and HVA in the hypothalamus, hippocampus, striatum, midbrain were assayed an hour after treatment using high performance liquid chromatography with electrochemical detection. It was found that 20 and 40 mg/kg of TC-2153 significantly increased 5-HT, 5-HIAA, DA and HVA levels as well as the HVA/DA ratio in the hypothalamus. At the same time, the drug produced no effect on 5-HT, 5-HIAA, DA and HVA levels in the hippocampus, striatum, midbrain or substantia nigra. Therefore, the hypothalamic 5-HT and DA systems are targets for acute TC-2153 injection.

Acetylcholinesterase (AChE) is an attractive target of drugs for Alzheimer’s disease (AD). A series of novel synthesized flavonoid derivatives have been reported as potent AChE inhibitors, but the lack of structure-AChE inhibitory activity relationships hampers the design of specific and selective flavonoid derivatives. In this study, 3D-quantitative structure activity relationship (3D-QSAR) models of 90 flavonoid derivatives as AChE inhibitors were established by using CoMFA and CoMSIA techniques. The results showed that both CoMFA model (q2= 0.651, r2= 0.939, F value = 173.5 and SEE=0.218 ) and CoMSIA model (q2= 0.680, r2= 0.947, F value = 151.8 and SEE=0.226) demonstrated statistically significant results and good predictive ability. Furthermore, docking studies were used for better understanding of the binding modes between flavonoid inhibitors and AChE. In conclusion, the essential information obtained from this study could provide valuable insight for further modification of highly potent AChE inhibitors.

Fluoroquinolones are well known and among most promising nitrogen containing heterocyclic compounds depicting broad spectrum and potent anti-infective activities. Numerous fluoroquinolone derivatives have been found to possess considerable favorable properties such as excellent bioavailability, good tissue penetrability and low toxic effects which attract the extensive research endeavors worldwide. With a better understanding of structure activity relationships of fluoroquinolones, it has been possible to develop superior compounds. This paper is an attempt to review the recent patents on these drugs with special emphasis on ciprofloxacin, norfloxacin, ofloxacin and moxifloxacin.

Drugs comprising a heterocyclic system show widespread therapeutic impact such as antimicrobial, antidepressant, antihypertensive, and anticancer activity. We describe herein computational studies that support the promising biological activity of four new compounds (5, 6, 10 and 13). The wild-type and mutant phosphatidylinositol-4,5-bisphosphate 3-kinaseα (PI3Kα) proteins were used as models to explore the potential interaction of the designed molecules with this important kinase involved in the growth regulation of cancer cells. The results of our studies showed that the verified compounds ought to fit into the kinase domain of wild-type and mutant PI3Kαs. It is predicted that they interact with S774, K802, Y836, V851, S854, T856, Q859, and D933 that are known to be key binding residues for active inhibitors both in wild-type and mutant PI3Kαs. Docking scores infer the selectivity of compounds 5, 6 and 10 toward the mutant PI3Kα (H1047R), whereas compound 13 displayed a slightly higher affinity to the wild-type protein. The pharmacophore modeling of PI3Kα inhibitors showed that the explored compounds shared four out of five pharmacophoric points with such inhibitors. Thus, the recently developed four compounds might be recruited as lead structures for the design of new antitumor drugs targeting PI3Kα.

A series of 2´-hydroxy-4´,6´-diisoprenyloxychalcone derivatives were synthesized and evaluated for inhibitory activities against CDC25B and PTP1B. The results displayed the most of them showed inhibitory activities against CDC25B (IC50=1.19–14.20 µg/mL) and PTP1B (IC50= 1.26–8.44µg /mL), respectively. Moreover, compound 2h displayed the most CDC25B and PTP1B inhibitory activity in vitro with IC50 values of 1.19 and 1.26 µg/mL, respectively, compared with reference drugs Na3VO4(IC50=1.09 µg/mL) and oleanolic acid (IC50=1.01 µg/mL). The results of selectivity experiments showed that the target compounds were selective inhibitors against CDC25B and PTP1B. Enzyme kinetic experiments demonstrated that compound 2h was a specific inhibitor with the typical characteristics of a mixed inhibitor.