Synthesis and Biological Evaluation of Distamycin Analogues – New Potential Anticancer Agents

Eight of analogues of distamycin, potential minor‐groove binders, were synthesized and tested for in‐vitro cytotoxicity towards human breast cancer cells MCF‐7 and MDA‐MB‐231. The method of synthesis is simple and convenient. All of the compounds 1 – 8 showed antiproliferative and cytotoxic effects against both cell lines in the range 3.47 to 12.53 μM for MDA‐MB‐231 and 4.35 to 12.66 μM for MCF‐7. All compounds demonstrated activity against DNA topoisomerases I and II at a concentration of 50 μM. The ethidium bromide assay showed that these compounds bind to plasmid pBR322, yet weaker than distamycin. Further investigations concerning the mechanism of cytotoxicity are now in progress, but the IC₅₀ values suggest that synthetic distamycin analogues with a free amino group, 3 – 4 and 7 – 8 , can serve as potential carriers of strong acting elements, e. g. alkylating groups.     

Synthesis,Molecular Docking,and Biological Evaluation of Some Novel Hydrazones and Pyrazole Derivatives as Anti‐inflammatory Agents

2‐Hydrazinyl‐N‐(4‐sulfamoylphenyl)acetamide 3 was the key intermediate for the synthesis of novel hydrazones 4–10 and pyrazole derivatives 11–17 . All compounds were tested for their in vivo anti‐inflammatory activity and their ability to inhibit the production of PGE₂ in serum samples of rats. IC₅₀ values for the most active compounds for inhibition of COX‐1 and COX‐2 enzymes were determined in vitro, and they were also tested for their ulcerogenic effect. Molecular docking was performed on the active site of COX‐2 to predict their mode of binding to the amino acids. Most of the synthesized compounds showed good anti‐inflammatory activity especially compounds 3, 4, 8, 9, 15, and 17 which showed better activity than diclofenac as the reference drug. Compounds 3, 8, 9, 13, and 15–17 were less ulcerogenic than indomethacine as the reference drug. Most of the synthesized compounds interacted with Tyr 385 and Ser 530 in molecular docking study with additional hydrogen bond for compound 17 . Compound 17 showed good selectivity index value of 11.1 for COX‐1/COX‐2 inhibition in vitro.     

Design,Synthesis, and Biological Evaluation of Pyrazole Derivatives

In this in vitro study, a series of novel pyrazole derivatives were designed, synthesized, and evaluated against five human cancer cell lines (PC3, A549, HL60, HCT116, and SW620) for their antiproliferative and p53‐MDM2 binding inhibitory activities. Although biological evaluations showed that this series of compounds possessed weak p53‐MDM2 inhibitory activities, most of them displayed moderate to potent antiproliferative activities against the tested cells lines. Compound 11c exhibited the best potency for MDM2 (FP‐IC₅₀ = 29.22 μm ) and demonstrated antiproliferative activities in response to the five tested cell lines (IC₅₀ = 4.09–16.82 μm ). Compared with the positive control Nutlin‐1, there was enhanced antiproliferative activity to p53‐mutated or p53‐deficient cell lines (SW620, HL60, and PC3).     

Evaluation of Ethanol and Aqueous extracts of Cinnamomum verum Leaf Galls for Potential Antioxidant and Analgesic activity

In the present study, ethanol and aqueous extracts of leaf galls of Cinnamomum verum were prepared to evaluate the antioxidant activity using 2,2-diphenyl-1-picrylhydrazyl free radical scavenging assay and superoxide radical scavenging assay with ascorbic acid as a standard, and analgesic activity by tail immersion test and acetic acid-induced writhing test methods using diclofenac sodium as the reference drug. Swiss albino mice maintained under standard laboratory conditions were used for analgesic tests. In the 2,2-diphenyl-1-picrylhydrazyl assay it was found that the aqueous and the ethanol extract possessed almost equal capacity to inhibit free radicals (IC₅₀=13.3 and 13.53 µg/ml) but found less than ascorbic acid (IC₅₀=9.96 µg/ml). And in superoxide assay the ethanol extract was found to be more potent in scavenging super oxide radicals when compared to ascorbic acid and the aqueous extract (IC₅₀=237.1 and 197.8 µg/ml) with the IC₅₀=119.7 µg/ml. For analgesic activity, ethanol extract showed the maximum time required for response against thermal stimuli (6.75±0.47 s) and maximum % of writhing inhibition (44.57%) when compared to aqueous extract (5.25±0.48 s and 32.61%), whereas diclofenac showed response in 7.25±0.25 s 67.39% inhibition in tail immersion and writhing tests, respectively. These results demonstrate that the ethanol extracts of leaf galls possessed high antioxidant and analgesic activity.     

Synthesis,Structural Characterization and Biological Evaluation of Novel Stilbene Derivatives as Potential Antimalarial Agents

A series of benzamide‐containing stilbene derivatives was synthesized through the incorporation of short basic side‐chains in the B‐ring hydroxy position of resveratrol. Their antiplasmodial activity was evaluated in vitro against the chloroquine resistant Plasmodium falciparum D10 strain, showing IC₅₀ values between 1.5 and 80 μm , while their cytotoxicity was assessed using an human myeloid leukemia (U‐937) cell line. With a selectivity ratio of >51.02, the most selective of these derivatives, 29, also had the most lowest cytotoxic activity of the series.     

Synthesis of Analogues of BCTC Incorporating a Pyrrolidinyl Linker and Biological Evaluation as Transient Receptor Potential Vanilloid 1 Antagonists

A series of novel pyrrolidinyl linker TRPV1 antagonists were prepared in an effort to lower the hyperthermic side‐effects of first‐generation antagonist BCTC. These compounds were investigated for antagonism of hTRPV1 activation by capsaicin and acid in vitro. Preliminary results suggested the compounds 10a , 10b , 10c and 10j had favorable TRPV1 antagonism activity. In further studies in vivo, 10b , comparable to BCTC, showed potent analgesic activity in capsaicin‐induced and heat‐induced pain models. In addition, 10b indicated a reduced risk of body temperature elevation. All of these demonstrated that 10b can be considered as a safe candidate for the further development of analgesic drugs.     

Synthesis and Anti-inflammatory Evaluation of New Sulfamoylheterocarboxylic Derivatives

A series of new sulfamoylthiophene and sulfamoylpyrazole carboxylic acid derivatives was synthesized. Some of these compounds show interesting analgesic properties and significant nonsteroidal anti-inflammatory activities in several models of inflammation.     

Synthesis and Biological Evaluation of Some Novel Polysubstituted Pyrimidine Derivatives as Potential Antimicrobial and Anticancer Agents

Synthesis and evaluation of the antimicrobial and cytotoxic activity of two series of polysubstituted pyrimidines comprising the thioether functionality and other pharmacophores, reported to contribute to various chemotherapeutic activities are described. All newly synthesized compounds were subjected to in‐vitro antibacterial and antifungal screening. Out of the compounds tested, 18 derivatives displayed an obvious inhibitory effect on the growth of the tested Gram‐positive and Gram‐negative bacterial strains, with special effectiveness against the Gram‐positive strains. Compounds 1 , 2 , 6 , 7 , 9 , 10 , 11 , 21 , and 24 revealed remarkable broad antibacterial spectrum profiles. Among those, compounds 1 , 2 , 6 , 7 , 9 , and 24 exhibited an appreciable antifungal activity against C. albicans. Compound 2 proved to be the most active antimicrobial member identified here as it showed twice the activity of ampicillin against B. subtilis and the same activity of ampicillin against M. Luteus and P. aeruginosa together with a moderate antifungal activity. Further, eleven analogs were evaluated for their in‐vitro cytotoxic potential utilizing the standard MTT assay against a panel of three human cell lines: breast adenocarcinoma MCF7, hepatocellular carcinoma HePG2, and colon carcinoma HT29. The obtained data revealed that six of the tested compounds 1 , 3 , 7 , 12 , 13 , and 15 showed a variable degree of cytotoxic activity against the tested cell lines at both the LC₅₀ and LC₉₀ levels. Compound 7 proved to be the most active cytotoxic member in this study with special effectiveness against the colon carcinoma HT29 and breast cancer MCF7 human cell lines for LC₅₀ and LC₉₀. Thus, compounds 1 and 7 could be considered as possible dual antimicrobial‐anticancer agents.     

Design,Synthesis, and Biological Evaluation of Prenylated Chalcones as Vasorelaxant Agents

Five prenylated chalcones and one allylated chalcone were prepared according to the analysis based on support vector machine (SVM) classification model. Most of the synthesized chalcones showed potent vasorelaxant activities through evaluation in aortic rings with the endothelium pre‐contracted by phenylephrine (PE), indicating that the experimental activities were in good agreement with the theoretical ones. Structure‐activity relationship of these compounds showed that the substituent pattern and number of hydroxyl groups were crucial for their vasorelaxant activities and that the replacement of prenyl group with allyl group retained the potent activity.     

Design,Synthesis, and Biological Evaluation of Novel Peptide Gly3‐MC62 Analogues as Potential Antidiabetic Agents

Two series of conformationally constrained analogues from Gly ³ ‐ MC 62 were designed by scanning the residues Lys¹, Thr², Met⁴, Lys⁵, Met^7, and Ala⁸ with an i‐(i + 2) lactam bridge consisting of a Glutamic acid–xaa–lysine (Glu–Xaa–Lys) scaffold and a diproline fragment. They were synthesized and evaluated for their antihyperglycemic effects. Through screening in normal and mice with diabetes mellitus, peptides II ‐5 , III ‐3 , III ‐4 , and III ‐5 showed significant improvement in antihyperglycemic and antioxidative activities compared with Gly ³ ‐ MC 62 , especially the compound III ‐4 . The primary mechanism of the compounds ( II ‐5 , III ‐3 , III ‐4 , and III ‐5 ) underlying this effect is the islet β‐cells against oxidative damage induced by STZ, and III ‐4 ‐treated mice showed considerable improvement in the preservation of beta cells in the pancreatic islets of DM mice. These data suggested that III ‐4 could be candidate for the future treatment of diabetes mellitus.     

Design,Synthesis, and Biological Evaluation of Andrographolide Derivatives as Potent Hepatoprotective Agents

Poor water solubility limits the clinical use of andrographolide and its derivatives. In an attempt to develop potent hepatoprotective drugs, a strategy was proposed to improve the aqueous solubility of andrographolide. Ten andrographolide derivatives were designed, synthesized, evaluated for aqueous solubility and in vivo hepatoprotective activity against CCl₄‐induced liver injury in mice. As expected, the aqueous solubility of synthetic derivatives was effectively improved. All compounds demonstrated the effect of different degrees in improving the liver enzyme (ALT and AST) activity, especially the most promising compound 9d significantly improved liver enzyme activity, with high potency to be a new lead.     

Synthesis and Evaluation of L-Glutamic acid Analogs as Potential Anticancer Agents

Four N-(benzenesulfonyl)-L-glutamic acid bis(p-substituted phenylhydrazides) were synthesized and evaluated for anticancer activity in vitro in DU-145 and PC-3 prostate cancer and in COLO-205 colon cancer cell lines by MTT assay. The analog with the nitro group substitution exhibited potent activity (% Inhibition 84.7 and 72.0 in DU-145 and PC-3 respectively at 80 μg/ml concentration). Another series of substituted 1-(benzenesulfonyl)-5-oxopyrrolidine 2-carboxamides (11a-f) were synthesized and evaluated for anticancer activity in vitro in colon (COLO-205), breast (Zr-75-1) and prostate (PC-3) cancer cell lines by MTT assay using adriamycin as standard. Test compounds 11a-c showed potent activity (% Inhibition 61.2 to 79.2 at 20 μg/ml and 67.2 to 87.2 at 40 μg/ml) in PC-3 cell line which is superior to the activity of Adriamycin. In comparison compounds 11d-f were less potent. In Zr-75-1 cell line 11a-e showed % inhibition ranging from 32.4 to 54.9 at 10 μg/ml concentration while in COLO-205 cell line 11a-f showed poor activity.     

Synthesis and Biological Evaluation of Mercapto Triazolo‐Benzothiadiazine Linked Aminobenzothiazoles as Potential Anticancer Agents

The synthesis of a series of 10‐substituted 5,5‐dioxo‐5,10‐dihydro[1,2,4]triazolo[4,3‐b][1,2,4]benzothiadiazine coupled with sulfanylacetamido benzothiazole pharmacophores ( 5a – g ) is described. All the synthesized compounds have been evaluated for their anticancer activity. Most of the compounds showed significant growth inhibitory activity against selected human tumor cell lines. Interestinlgy, one of the synthesized compounds 5d, exhibited GI₅₀ values of 1.4 and 2.1 μm against RPMI‐8226 (leukemia) and HOP‐62 (lungs) cell lines, respectively.     

Design,Synthesis, and Biological Evaluation of Scutellarein Carbamate Derivatives as Potential Multifunctional Agents for the Treatment of Alzheimer's Disease

A series of scutellarein carbamate derivatives were designed and synthesized based on the multitarget‐directed drug design strategy for treatment of Alzheimer's disease. Their acetylcholinesterase and butyrylcholinesterase inhibitory activities, antioxidant activities, metals chelation, and neuroprotective effects against hydrogen peroxide‐induced PC12 cell injury were evaluated in vitro. The preliminary results indicated that compound 7b exhibited good inhibitory potency toward AChE and BuChE with IC₅₀ values of 1.2 ± 0.03 μm and 22.1 ± 0.15 μm , respectively, possessed the strong antioxidant potency (10.3 trolox equivalents), as well as acted as a selective metal chelator and neuroprotective agent. Furthermore, 7b could improve memory impairment induced by scopolamine, ethanol, and sodium nitrite using the step‐down passive avoidance task in vivo and could remarkably decrease the activity of acetylcholinesterase in mice brain. This study indicated that 7b could be considered as a potential multitarget agent against AD.     

Analgesic and anti-inflammatory activity of amifostine, DRDE-07, and their analogs, in mice

Objectives:

To find out the analgesic and anti-inflammatory activity, if any, of Amifostine [S-2(3 amino propyl amino) ethyl phosphorothioate], DRDE-07 [S-2(3 amino ethyl amino) ethyl phenyl sulphide] and their analogs DRDE-30 and DRDE-35, the probable prophylactic agent for sulphur mustard (SM).

Materials and Methods:

In order to find out the analgesic activities of the compounds two methods were employed, namely, acetic acid-induced writhing test and formalin-induced paw licking. The persistent pain model of formalin-induced hind paw licking was carried out to test the effect of the compounds on neurogenic pain or early phase (0 to 5 minutes) and on the peripheral pain or the late phase (15 to 30 minutes). To test the effect of the compound in acute inflammation, carrageenan-induced hind paw edema was carried out. This model of inflammation involves a variety of mediators of inflammation.

Results:

DRDE-07 (81.7%) and DRDE-30 (79.4%) showed significant reduction in the acetic acid-induced writhing test. DRDE-07 (93.1%), DRDE-30 (82%), and DRDE-35 (61.3%) showed significant reduction in the second or late phase of formalin-induced paw licking. All the analogs (more than 60%) including amifostine (43.9%) showed significant reduction of paw edema in the carrageenan-induced paw edema in mice.

Conclusion:

The analgesic and anti-inflammatory activity of the antidotes were comparable with aspirin.     

Synthesis of Some Novel 2-[2-(aroyl-aroxy)-methyl]-4-phenyl-1,3-thiazoles as Potent Anti-Inflammatory Agents

A series of 2-[2-(aroyl-aroxy)-methyl]-4-phenyl-1,3-thiazoles 4a–j were obtained via multiple step synthesis sequence beginning with the hydroxybenzophenones (1a–g). Hydroxybenzophenones on reaction with chloroacetonitrile affords [(2-benzoyl) phenoxy] acetonitrile (2a–g), which reacts with H₂S/NH₄OH and yields [(2-benzoyl) phenoxy] acetothiamide (3a–g), which on treatment with phenacylbromides affords 2-[2-(aroyl-aroxy)-methyl]-4-phenyl-1,3-thiazoles (4a–j). All the newly synthesized compounds were evaluated for their anti-inflammatory activity and were compared with standard drugs. Of the compounds studied, (4g), compounds with chloro substituents showed more potent activity than the standard drug phenyl butazone at all doses tested.     

Synthesis and Biological Evaluation of Sophoridinol Derivatives as a Novel Family of Potential Anticancer Agents

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