Synthesis and evaluation of anticancer, antiphospholipases, antiproteases, and antimetabolic syndrome activities of some 3H-quinazolin-4-one derivatives.

Some new 3H-quinazolin-4-one derivatives were synthesised and screened for anticancer, antiphospholipases, antiproteases, and antimetabolic syndrome activities. Compound 15d was more potent in reducing the cell viabilities of HT-29 and SW620 cells lines to 38%, 36.7%, compared to 5-FU which demonstrated cell viabilities of 65.9 and 42.7% respectively. The IC50 values of 15d were ∼20 µg/ml. Assessment of apoptotic activity revealed that 15d decreased the cell viability by down regulating Bcl2 and BclxL. Moreover, compounds, 8j, 8d/15a/15e, 5b, and 8f displayed lowered IC50 values than oleanolic acid against proinflammatory isoforms of hGV, hG-X, NmPLA2, and AmPLA2. In addition, 8d, 8h, 8j, 15a, 15b, 15e, and 15f showed better anti-α-amylase than quercetin, whereas 8g, 8h, and 8i showed higher anti-α-glucosidase activity than allopurinol. Thus, these compounds can be considered as potential antidiabetic agents. Finally, none of the compounds showed higher antiproteases or xanthine oxidase activities than the used reference drugs.

Symmetric molecules with 1,4-triazole moieties as potent inhibitors of tumour-associated lactate dehydrogenase-A.

A series of symmetric molecules incorporating aryl or pyridyl moieties as central core and 1,4-substituted triazoles as a side bridge was synthesised. The new compounds were investigated as lactate dehydro-genase (LDH, EC 1.1.1.27) inhibitors. The cancer associated LDHA isoform was inhibited with IC50 = 117-174 µM. Seven compounds exhibited better LDHA inhibition (IC50 117-136 µM) compared to known LDH inhibitor - galloflavin (IC50 157 µM).

Novel quinazoline and acetamide derivatives as safe anti-ulcerogenic agent and anti-ulcerative colitis activity.

Two novel quinazoline derivatives named as; 3-[(4-hydroxy-3-methoxy-benzylidene)-amino]-2-p-tolyl-3H-quinazolin-4-one (5) and 2-p-Tolyl-3-[3,4,5-trimethoxy-benzylidene-amino]-3H-quinazolin-4-one (6) in addition to one acetamide derivative named as 2-(2-Hydroxycarbonylphenylamino)-N-(4-aminosulphonylphenyl) 11 were synthesized, and evaluated for their anti-ulcerogenic & Anti-Ulcerative colitis activities. All of the three compounds showed curative activity against acetic acid induced ulcer model at a dose of 50 mg/kg, they produced 65%, 85% & 57.74% curative ratio for compounds 5, 6 & 11 respectively. The effect of the tested compounds 5, 6 & 11 at dose 50 mg/kg were significantly (P < 0.01) more effective than dexamesathone (0.1 mg/kg) in reducing all parameters. Compounds showed curative activity of for peptic ulcer (induced by absolute alcohol (at a dose of 50 mg/kg, it produced Curative of control ulcer 56.00%, 61.70% & 87.1% for compounds 5, 6 & 11 respectively at dose 50 mg/kg, while the standard drug (Omeprazole 20 mg/kg) produced 33.3%. In both tests, the activity of our target compounds were higher than the standard drugs used for treatment of peptic ulcer and ulcerative colitis. No side effects were reported on liver and kidney functions upon prolonged oral administration of this compounds.

New quinoxalinone inhibitors targeting secreted phospholipase A2 and α-glucosidase.

Elevated blood glucose and increased activities of secreted phospholipase A2 (sPLA2) are strongly linked to coronary heart disease. In this report, our goal was to develop small heterocyclic compound that inhibit sPLA2. The title compounds were also tested against α-glucosidase and α-amylase. This array of enzymes was selected due to their implication in blood glucose regulation and diabetic cardiovascular complications. Therefore, two distinct series of quinoxalinone derivatives were synthesised; 3-[N'-(substituted-benzylidene)-hydrazino]-1H-quinoxalin-2-ones 3a-f and 1-(substituted-phenyl)-5H-[1,2,4]triazolo[4,3-a]quinoxalin-4-ones 4a-f. Four compounds showed promising enzyme inhibitory effect, compounds 3f and 4b-d potently inhibited the catalytic activities of all of the studied proinflammatory sPLA2. Compound 3e inhibited α-glucosidase (IC50 = 9.99 ± 0.18 µM); which is comparable to quercetin (IC50 = 9.93 ± 0.66 µM), a known inhibitor of this enzyme. Unfortunately, all compounds showed weak activity against α-amylase (IC50 > 200 µM). Structure-based molecular modelling tools were utilised to rationalise the SAR compared to co-crystal structures with sPLA2-GX as well as α-glucosidase. This report introduces novel compounds with dual activities on biochemically unrelated enzymes mutually involved in diabetes and its complications.

Anti-ulcerogenic and anti-ulcerative colitis (UC) activities of seven amines derivatives.

The Novel target compounds (CP-1-7) were synthesized and tested at doses up to 1000 mg/kg for their entitled activities. They exerted promising results without any behavioral changes and mortality in mice. Therefore, according to the results obtained in our study, it could be categorized as highly safe agents for treating UC since substances possessing LD50 higher than 50 mg/kg are considered nontoxic. They also possessed a potent anti-ulcerogenic activity with different potentials. The most effective compound was CP-4, it produced 97.7% ulcer protection of control followed by CP-3, which produced 90.3% protection, while the standard drug ranitidine (100 mg/kg) produced 49.2% protection. Compound CP-1 showed lowest activity among the current series, it produced 55.5% protection. The target compounds were significantly more effective than the standard in reducing ulcer index. The anti-ulcerative colitis activity was tested using acetic acid induced colitis model. The curative effect of the tested compounds at a dose of 50 mg/kg oral administration on rats showed a potent anti-ulcerative colitis activity with different potentials. They induced a significant decrease in ulcer score, ulcer area, ulcer index and weight/length of the colon specimens. The percent protection of control colitis ranged from 66.8% for CP-7 to 22.3% for CP-5; however the percent protection for dexamesathone (0.1 mg/kg) was 59.3%. The effect of the tested compounds CP-7 and CP-3 at dose 50 mg/kg were significantly more effective than dexamesathone (0.1 mg/kg) in reducing all parameters. Liver functions were not affected as there is no effect on the activity of both AST and ALT in animals that received the compounds, so the compounds didn't reveal hepatotoxic manifestation. Although, the results on kidney functions showed that, CP-1 slightly elevated blood urea concentration and CP-3 & CP-4 slightly elevated serum creatinine; no apparent nephrotoxic manifestations were recorded.

Novel essential amino acid-sulfanilamide hybrid as safe anti-ulcerogenic agent with anti-helicobacter pylori activity.

A novel and safe essential amino acid (Leucine) incorporating sulfanilamide was synthesized, and evaluated for its anti-ulcerogenic activity and in vitro anti-Helicobacter pylori activity. The new molecule showed a dose dependent activity against absolute ethanol-induced ulcer in rats, it produced percent protection of control ulcer by 66.7 at dose 100 mg/kg. In addition it showed a potent anti-Helicobacter pylori activity in vitro against 7 clinically isolated strains. The minimum inhibitory concentration (MIC) ranged from 12.5 to 50 µg/ml. The preliminary safety studies and toxicity profile are optimistic and encouraging.

Development of 3-(4-aminosulphonyl)-phenyl-2-mercapto-3H-quinazolin-4-ones as inhibitors of carbonic anhydrase isoforms involved in tumorigenesis and glaucoma.

A series of heterocyclic benzenesulfonamides incorporating 2-mercapto-3H-quinazolin-4-one tails were prepared by condensation of substituted anthranilic acids with 4-isothiocyanato-benzenesulfonamide. These sulfonamides were investigated as inhibitors of the human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms hCA I and II (cytosolic isozymes), as well as hCA IX and XII (trans-membrane, tumor-associated enzymes). They acted as medium potency inhibitors of hCA I (KIs of 81.0-3084 nM), being highly effective as hCA II (KIs in the range of 0.25-10.8 nM), IX (KIs of 3.7-50.4 nM) and XII (KIs of 0.60-52.9 nM) inhibitors. These compounds should thus be of interest as preclinical candidates in pathologies in which the activity of these enzymes should be inhibited, such as glaucoma (CA II and XII as targets) or some tumors in which the activity of three isoforms (CA II, IX and XII) is dysregulated.

Synthesis 4-[2-(2-mercapto-4-oxo-4H-quinazolin-3-yl)-ethyl]-benzenesulfonamides with subnanomolar carbonic anhydrase II and XII inhibitory properties.

Condensation of substituted anthranilic acids with 4-isothiocyanatoethyl-benzenesulfonamide led to series of heterocyclic benzenesulfonamides incorporating 2-mercapto-quinazolin-4-one tails. These sulfonamides were investigated as inhibitors of the human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms hCA I and II (cytosolic isozymes), as well as hCA XII (a transmembrane, tumor-associated enzyme also involved in glaucoma-genesis). The new sulfonamides acted as medium potency inhibitors of hCA I (KIs of 28.5-2954nM), being highly effective as hCA II (KIs in the range of 0.62-12.4nM) and XII (KIs of 0.54-7.11nM) inhibitors. All substitution patterns present in these compounds (e.g., halogens, methyl and methoxy moieties, in positions 6, 7 and/or 8 of the 2-mercapto-quinazolin-4-one ring) led to highly effective hCA II/XII inhibitors. These compounds should thus be of interest as preclinical candidates in pathologies in which the activity of these enzymes should be inhibited, such as glaucoma (CA II and XII as targets) or some tumors in which the activity of isoforms CA II and XII is dysregulated.

Synthesis, Antiphospholipase A2, Antiprotease, Antibacterial Evaluation and Molecular Docking Analysis of Certain Novel Hydrazones.

Some novel hydrazone derivatives 6a-o were synthesized from the key intermediate 4-Chloro-N-(2-hydrazinocarbonyl-phenyl)-benzamide 5 and characterized using IR, ¹H-NMR, 13C-NMR, mass spectroscopy and elemental analysis. The inhibitory potential against two secretory phospholipase A2 (sPLA2), three protease enzymes and eleven bacterial strains were evaluated. The results revealed that all compounds showed preferential inhibition towards hGIIA isoform of sPLA2 rather than DrG-IB with compounds 6l and 6e being the most active. The tested compounds exhibited excellent antiprotease activity against proteinase K and protease from Bacillus sp. with compound 6l being the most active against both enzymes. Furthermore, the maximum zones of inhibition against bacterial growth were exhibited by compounds; 6a, 6m, and 6o against P. aeruginosa; 6a, 6b, 6d, 6f, 6l, 6m, 6n, and 6o against Serratia; 6k against S. mutans; and compounds 6a, 6d, 6e, 6m, and 6n against E. feacalis. The docking simulations of hydrazones 6a-o with GIIA sPLA2, proteinase K and hydrazones 6a-e with glutamine-fructose-6-phosphate transaminase were performed to obtain information regarding the mechanism of action.

Synthesis, analgesic, anti-inflammatory and anti-ulcerogenic activities of certain novel Schiff's bases as fenamate isosteres.

A series of certain novel Schiff bases as fenamate isosteres (VI:a-k) were synthesized to locate analgesic, anti-inflammatory agent with minimal ulcerogenic potential. The structures of the newly synthesized compounds were elucidated on the basis of their elemental analysis as well as IR, and NMR and mass spectroscopic data. All the compounds were evaluated for their anti-inflammatory activity by carrageenan induced paw oedema method. The compounds possessing good anti-inflammatory activity were further tested for analgesic, ulcerogenic, lipid peroxidation potentials and liver toxicity. Compounds (VI-c), (VI-f), (VI-h) and (VI-i) showed the best anti-inflammatory and significant analgesic activities at doses comparable to that of the standard drug Indomethacin. However, compounds (VI-c) and (VI-f) could be considered the most potent anti-inflammatory and analgesic molecules with maximum reduction in gastro-intestinal ulceration with no hepatocyte necrosis or liver degeneration.

Benzenesulfonamides incorporating bulky aromatic/heterocyclic tails with potent carbonic anhydrase inhibitory activity.

Three series of sulfonamides incorporating long, bulky tails were obtained by applying synthetic strategies in which substituted anthranilic acids, quinazolines and aromatic sulfonamides have been used as starting materials. They incorporate long, bulky diamide-, 4-oxoquinazoline-3-yl- or quinazoline-4-yl moieties in their molecules, and were investigated for the inhibition of four physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isoforms, the cytosolic human (h) hCA I and II, as well as the transmembrane hCA IX and XII. Most of the new sulfonamides showed excellent inhibitory effects against the four isoforms, with KIs of 7.6-322nM against hCA I, of 0.06-85.4nM against hCA II; of 6.7-152nM against hCA IX and of 0.49-237nM against hCA XII; respectively. However no relevant isoform-selective behavior has been observed for any of them, although hCA II and XII, isoforms involved in glaucoma-genesis were the most inhibited ones. The structure-activity relationship for inhibiting the four CAs with these derivatives is discussed in detail.

Design, synthesis, and antitumor screening of certain novel tetrahydroquinoline sulfonamides.

Sulfonamide containing molecules are of sound biomedical interest. This work comprises the synthesis and in vitro antitumor testing of new library of 20 such molecules. These compounds were screened for cytotoxic activity against three tumor cell lines MCF-7, HeLa, and HepG2 using MTT assay. The yield was low but all the target compounds exhibited antiproliferative activity better than the standard drug Doxorubicin (CAS-23214-92-8). Seven compounds were more potent and four compounds were as active as the standard drug. There were no great difference between compounds obtained from dimedone and those obtained from cyclohexandione. Also no significant difference found in activity between compounds bearing o-amino ethyl ester side chain and compounds bearing o-amino amide derivatives. However, compounds bearing o-amino-cyano group, although retained considerable activity they were far less active than the preceding two. It was clear that monohydroxy aldehyde derivatives were less active compared with the di and trihydroxy ones.

Inhibition studies of quinazoline-sulfonamide derivatives against the γ-CA (PgiCA) from the pathogenic bacterium, Porphyromonas gingivalis.

Carbonic anhydrases (CAs, EC 4.2.1.1) began to be investigated in detail in pathogenic bacteria, in the search for antibiotics with a novel mechanism of action, since it has been demonstrated that in many bacteria CAs are essential for the life cycle of the organism. The presence of CAs in pathogenic bacteria allows the development of anti-infectives with a new mechanism of action, less explored to date. Here, novel quinazoline derivatives crowned with sulfonamide functionality at position-2 were tested for their ability to inhibit the bacterial γ-CA (PgiCA), identified in the genome of Porphyromonas gingivalis. Six compounds were highly effective, nanomolar inhibitors of the pathogenic enzyme γ-PgCA. Three of them were also highly effective sub-nanomolar inhibitors of the cytosolic human isoform II (hCAII). The best γ-PgCA inhibitor was compound 8c, with a K(I) of 3.53 nM and selectivity ratio of 24.5 and 24.8 against hCA I and hCA II, respectively. Many of these new compounds showed a high selectivity for bacterial enzyme respect to the mammalian CA isoforms (hCAI and hCAII). These results suggest that sulfonamides with quinazoline scaffold could be considered as suitable candidates for further derivatization to better understand the role of bacterial CAs in pathogenesis.

A new class of quinazoline-sulfonamides acting as efficient inhibitors against the α-carbonic anhydrase from Trypanosoma cruzi.

The protozoan parasite Trypanosoma cruzi is the agent responsible for trypanosomiasis (Chagas disease) in humans and other animals. It has been recently reported that this pathogen encodes for an α-class carbonic anhydrase (CA, EC 4.2.1.1), denominated TcCA, which was shown to be crucial for its life cycle. Inhibition studies of a class of 4-oxoquinazoline containing a benzensulfonamide moiety and their 4-thioxo bioisosteres against the protozoan enzyme TcCA are described here. Most of 4-oxoquinazoline sulfonamides showed nanomolar TcCA inhibition activity with K(I)s in the same order of magnitude of acetazolamide (AAZ), whereas their thioxo bioisosters showed moderate anti-Trypanosoma CA potency with K(I)s in the micromolar range. The discovery of compounds incorporating a 4-oxoquinazoline ring as a low-nanomolar TcCA inhibitor is quite promising and it may be useful for developing anti-Trypanosoma agents with a novel mechanism of action compared to the clinically used drugs (such as benznidazole, nifurtimox) for which significant resistance and serious adverse effects due to their high-toxicity appeared.

Inhibition of human carbonic anhydrase isozymes I, II, IX and XII with a new series of sulfonamides incorporating aroylhydrazone-, [1,2,4]triazolo[3,4-b][1,3,4]thiadiazinyl- or 2-(cyanophenylmethylene)-1,3,4-thiadiazol-3(2H)-yl moieties.

A series of benzenesulfonamides incorporating aroylhydrazone, piperidinyl, sulfone, [1,2,4]triazolo[3,4-b][1,3,4]thiadiazinyl- or 2-(cyanophenyl-methylene)-1,3,4-thiadiazol-3(2H)-yl moieties was investigated as inhibitors of four α-carbonic anhydrases (CAs, EC 4.2.1.1), the human (h) isoforms hCA I, II (cytosolic, offtarget enzymes) and hCA IX and XII (transmembrane, tumor-associated isoforms). Low nanomolar activity was observed against hCA II (KIs of 0.56-17.1 nM) with these sulfonamides, whereas the slow cytosolic isoform hCA I was less inhibited by these compounds (KIs of 86.4 nM-32.8 µM). Most of these sulfonamides significantly inhibited CA IX, with KIs in the range of 4.5-47.0 nM, although some of the derivatives incorporating bulkier bicyclic moieties, as well as 2-thienyl fragments, showed a weaker activity against this isoform (KIs in the range 50.1-553 nM). All the investigated compounds also inhibited CA XII with KIs in the range 0.85-376 nM. The best inhibitors were those incorporating bulky [1,2,4]triazolo[3,4-b][1,3,4]thiadiazinyl moieties and 1,3,4-thiadiazol-3(2H)-yl groups.

Prophylactic and curative anti-ulcerative colitis activity and the possible mechanisms of action of some desert plants.

The aim of the present study was to evaluate both prophylactic and curative anti-ulcerative colitis activity and the possible mechanism of action of seven desert plant extracts. Seven desert plants from different families; Conyza dioscoridis (L.) Desf. (Asteraceae), Euphorbia hirta L. (Euphorpiaceae), Origanum syriacum L. and Salvia lanigera L. (Lamiaceae), Sisymbrium irio L., Solanum nigrum Linn. (Solanaceae) and Solenostemma arghel (Del.) Hayne. (Asclepiadaceae) were separately evaluated at three doses (125, 250, and 500 mg/kg) using the acetic acid-induced colitis model. The investigated extracts possessed prophylactic and curative anti-ulcerative colitis activities in a dose-dependent manner, where Salvia lanigera (87.9) and Solenostemma arghel (89.2) were the most effective extracts whereas the dexamesathone produced 68%. These extracts were further investigated for estimation of their mechanism of action. The in vitro potential radical (DPPH) scavenging activities of the investigated extracts were well supported with the reduction of colonic MDA content for both extracts. Suppression of the inflammatory mediator TNF-α and inhibition of both PLA2 and protease enzymes may play an important role in the anti-ulcerative colitis activities. The investigated extracts were safe for use up to 5 g/kg and the total alcohol extracts of Salvia lanigera and Solenostemma arghel (400 mg/kg for 35 d) showed no alteration on liver and kidney functions. Phytochemical screening of the investigated extracts revealed the presence of flavonoids, tannins, unsaturated sterols, and proteins which could be responsible for the activities.

Synthesis and biological evaluation of certain 3-substituted benzylideneamino-2-(4-nitrophenyl)quinazolin-4(3H)-one derivatives.

Certain new 3H-quinazolin-4-one Schiff's bases were synthesized and screened for their activities against ulcerative colitis "UC". Their activity against phospholipase A2 and protease enzymes was also investigated. Some compounds possessed remarkable effect with different potentials against acetic acid-induced colitis model in rats. Compound 14 (50 mg/kg) was more effective than dexamesathone (0.01 mg/kg). It produced 79.78% protection of control colitis; however, compound 13 produced 75.80% protection and was considered as effective as dexamesathone with 75.30% protection. The observed results could be explained partially by their anti-inflammatory activities which appear as phospholipase A2 (hGIIA) and/or through protease inhibitor potentials. However, all the compounds under test showed preferential inhibition towards hG-IIA type of PLA2 rather than DrG-IB with varying degrees. Interestingly, compounds 14, 13, 12 and 11 displayed excellent inhibitory activity against phospholipase A2 accompanied by protease inhibitory profile.

Exploring QSARs of some benzenesulfonamides incorporating cyanoacrylamide moieties as a carbonic anhydrase inhibitors (specifically against tumor-associated isoforms IX and XII).

Benzenesulfonamides incorporating cyanoacrylamide moieties with activity against tumour-associated human (h) isoforms hCA IX and XII (which are validated antitumor targets) were investigated for their quantitative structural activity relationships (QSAR). Multiple linear regression analysis was used to develop model relationships between molecular descriptors and inhibition constants (Ki). The molecular geometry optimization were performed on all molecules at DFT-B3LYP/6-311++G(d,p) level. Over 1250 molecular descriptors were calculated using Gaussian 09, Hyperchem and EDRAGON programs. Multiple linear regression equations have been developed and validated using leave-one-out cross-validated technique. The derived QSAR models are found to be statistically significant and show good predictive ability.

New Activities for Isolated Compounds from Convolvulus austro-aegyptiacus as Anti-ulcerogenic, Anti-Helicobacter pylori and Their Mimic Synthesis Using Bio-guided Fractionation.

Bio-guided fractionation of the total alcoholic extract of Convolvulus austro-aegyptiacus was screened for its anti-ulcerogenic activity, using an absolute-ethanol-induced ulcer model at 500 and 1000 mg/kg doses. Two compounds were isolated from the butanol extract of C. austro-aegyptiacus and identified by 1 H and 13 C nuclear magnetic resonance as scopoletin and scopolin. The isolated compounds (50 mg/kg) showed a remarkable anti-ulcerogenic activity because they exhibited control-ulcer protection by 16.7% and 90.8%, respectively. The acute toxicity study showed that the extract is highly safe; the median lethal dose (LD50) was more than 4000 mg/kg. Moreover, the obtained results were confirmed by the sub-chronic toxicity because the rats that have been administered 1000 mg/kg of the extract for 15 consecutive days showed no alteration in the liver and kidney functions. Copyright © 2015 John Wiley & Sons, Ltd.

Synthesis and Evaluation of Selected Benzimidazole Derivatives as Potential Antimicrobial Agents.

A library of 53 benzimidazole derivatives, with substituents at positions 1, 2 and 5, were synthesized and screened against a series of reference strains of bacteria and fungi of medical relevance. The SAR analyses of the most promising results showed that the antimicrobial activity of the compounds depended on the substituents attached to the bicyclic heterocycle. In particular, some compounds displayed antibacterial activity against two methicillin-resistant Staphylococcus aureus (MRSA) strains with minimum inhibitory concentrations (MICs) comparable to the widely-used drug ciprofloxacin. The compounds have some common features; three possess 5-halo substituents; two are derivatives of (S)-2-ethanaminebenzimidazole; and the others are derivatives of one 2-(chloromethyl)-1H-benzo[d]imidazole and (1H-benzo[d]imidazol-2-yl)methanethiol. The results from the antifungal screening were also very interesting: 23 compounds exhibited potent fungicidal activity against the selected fungal strains. They displayed equivalent or greater potency in their MIC values than amphotericin B. The 5-halobenzimidazole derivatives could be considered promising broad-spectrum antimicrobial candidates that deserve further study for potential therapeutic applications.