Dapson in heterocyclic chemistry part VI: synthesis and molecular docking of some novel sulfonebiscompounds of expected anticancer activity.

To discover new bioactive lead compounds for medicinal purposes, herein, sulfone biscompounds bearing dihydrothiazoles (3-9, 14, 15), acrylamide (11), thiazolidinones (12, 13, 20), thiophenes (16, 17) and benzothiophene (19) were prepared and tested for their anticancer activity. The structures of the products were confirmed from elemental analysis as well as spectral data. All the synthesized compounds showed remarkable anticancer activity against human breast cancer cell line especially, compound (3) with IC50 value 23.02 µM which was better than that of Doxorubicin by three folds. In order to elucidate the mechanism of action of their cytotoxic activity molecular docking on the active sites of farnesyl transferase and arginine methyl transferase was performed for all synthesized compounds and good results were obtained.

Comparative bioavailability study of cefixime (equivalent to 100 mg/5 ml) suspension (Winex vs Suprax) in healthy male volunteers.

This investigation was carried out to evaluate the bioavailability of a new suspension formulation of cefixime (100 mg/5 ml), Winex, relative to the reference product, Suprax (100 mg/5 ml) suspension. The bio-availability study was carried out in 24 healthy male volunteers who received a single oral dose (200 mg) of the test (A) and the reference (B) products on 2 treatment days after an overnight fast of at least 10 hours. The treatment periods were separated by a one-week washout period. A randomized, balanced two-way crossover design was used. After dosing, serial blood samples were collected over a period of 16 hours. Plasma concentrations of cefixime were analyzed using a sensitive high-performance liquid chromatographic assay. The pharmacokinetic parameters for cefixime were determined using standard non-compartmental method. The parameters AUC(0-t), AUC(0-infinity), Cmax, Kel, t1/2 and Cmax/AUC(0-infinity) were analyzed statistically using raw and log-transformed data. The time to maximum concentration (tmax) was analyzed using raw data. The parametric 90% confidence intervals of the mean values of the pnfinity harmacokinetic parameters: AUC(0-t), AUC(0-infinity) Cmax, and Cmax/AUC(0-infinity) were within the range 80 - 125% which is acceptable for bioequivalence (using log-transformed data). The calculated 90% confidence intervals based on the ANOVA analysis for the mean test/reference ratios of AUC(0-t), AUC(0-infinity), Cmax, and Cmax/AUC(0-infinity) were 88.93 - 107.10%, 89.09 - 107.11%, 89.63 - 108.58% and 96.85 - 105.29%, respectively. The test formulation was found bioequivalent to the reference formulation with regard to AUC(0-t), AUC(0-infinity), and Cmax using the Schuirmann's two one-sided t-tests. Therefore, the two formulations were considered to be bioequivalent.

Comparative bioavailability study of doxycycline hyclate (equivalent to 100 mg doxycycline) capsules (doxycin vs vibramycin) for bioequivalence evaluation in healthy adult volunteers.

This investigation was carried out to evaluate the bioavailability of a new capsule formulation of doxycycline (100 mg), doxycin, relative to the reference product, vibramycin (100 mg) capsules. The bioavailability was carried out in 24 healthy male volunteers who received a single dose (100 mg) of the test (A) and the reference (B) products after an overnight fast of at least 10 hours on 2 treatment days. The treatment periods were separated by a 2-week washout period. A randomized, balanced 2-way cross-over design was used. After dosing, serial blood samples were collected for a period of 48 hours. Plasma concentrations of doxycycline were analyzed by a sensitive and validated high-performance liquid chromatography assay. The pharmacokinetic parameters for doxycycline were determined using standard noncompartmental methods. The parameters AUC(0-t), AUC(0-infinity), Cmax, K(el), t(1/2) and Cmax/AUC(0-infinity) were analyzed statistically using log-transformed data. The time to maximum concentration (tmax) was analyzed using raw data. The parametric 90% confidence intervals of the mean values of the pharmacokinetic parameters: AUC(0-t), AUC(0-infinity), Cmax and Cmax/AUC(0-infinity) were within the range 80-125% which is acceptable for bioequivalence (using log-transformed data). The calculated 90% confidence intervals based on the ANOVA analysis of the mean test/reference ratios of AUC(0-t), AUC(0-infinity), Cmax and Cmax/AUC(0-infinity) were 95.98-109.56%, 92.21 to 107.66%, 93.90-112.56%, and 96.0 to 106.91% respectively. The test formulation was found bioequivalent to the reference formulation with regard to AUC(0-t), AUC(0-infinity), Cmax and Cmax/AUC(0-infinity) by the Schuirmann's two 1-sided t-tests. Therefore, the 2 formulations were considered to be bioequivalent.

Hepatoprotective properties of Commiphora opobalsamum ("Balessan"), a traditional medicinal plant of Saudi Arabia.

The hepatoprotective activity of an ethanolic extract of Commiphora opobalsamum ("Balessan") was investigated in rats by inducing hepatotoxicity with carbon tetrachloride:liquid paraffin (1:1). This extract has been shown to possess significant protective effect by lowering serum transaminase levels (serum glutamate oxaloacetate transaminase and serum glutamate pyruvate transaminase), alkaline phosphatase and bilirubin. Pretreatment with an extract of Balessan prevented the prolongation of the barbiturate sleeping time associated with carbon tetrachloride-induced liver damage in mice. On the other hand, CCl4-induced low-level nonprotein sulfhydryl concentration in the liver was replenished by the Balessan extract. These data suggest that the plant C. opobalsamum may act as an antioxidant agent and may have a hepatoprotective effect.

Daucane sesquiterpenes from Ferula hermonis.

The roots of Ferula hermonis Boiss yielded two new daucane esters, 14-(4'-hydroxybenzoyloxy)dauc-4,8-diene (1) and 14-(4'-hydroxy-3'-methoxybenzoyloxy)dauc-4,8-diene (2), together with the four known sesquiterpenes jaeschkeanadiol p-hydroxybenzoate (3), jaeschkeanadiol benzoate (4), jaeschkeanadiol (5), and epoxyjaeschkeanadiol (6). The identities of the isolated compounds were ascertained primarily using NMR and MS data. Compounds 1 and 3 exhibited antimicrobial activity against Staphylococcus aureus with IC(50) 1.5 and 3.5 microg/mL, respectively, and against Methicillin-resistant S. aureus with IC(50) 2.0 and 4.0 microg/mL, respectively.

New quinoline alkaloids from Ruta chalepensis.

The roots of Ruta chalepensis, collected from the northern Saudi desert, yielded two new quinoline alkaloids, namely, 2-¿6'-(2H-benzo[d]1' ',3' '-dioxolen-5' '-yl)hexyl¿-hydroquinolin-4-one (1) and 2-¿6'-(2H-benzo[d]1' ',3' '-dioxolen-5' '-yl)hexyl¿-4-methoxy-quinoline (2). Nine previously reported alkaloids, dictamnine, pteleine, skimmianine, rutacridone, isogravacridonechlorine, maculosidine, graveoline, graveolinine, and 4-methoxy-1-methyl-2(1H)-quinolinone, and coumarins, chalepensin, and umbelliferone were also isolated. Structure elucidations were based primarily on 1D and 2D NMR analyses and chemical transformations. Antimicrobial activity of these compounds is discussed.

Bioactive 12-oleanene triterpene and secotriterpene acids from Maytenus undata.

The aerial parts of Maytenus undata yielded four new 12-oleanene and 3,4-seco-12-oleanene triterpene acids, namely, 3-oxo-11alpha-methoxyolean-12-ene-30-oic acid (1), 3-oxo-11alpha-hydroxyolean-12-ene-30-oic acid (2), 3-oxo-olean-9(11), 12-diene-30-oic acid (3), and 3,4-seco-olean-4(23),12-diene-3, 29-dioic acid (20-epi-koetjapic acid) (5), together with the known 3, 11-dioxoolean-12-ene-30-oic acid (3-oxo-18beta-glycyrrhetinic acid) (4), koetjapic acid (6), and the 12-oleanene artifact 3-oxo-11alpha-ethoxyolean-12-ene-30-oic acid (7). Koetjapic acid (6) inhibited the growth of Staphylococcus aureus, methicillin-resistant S. aureus, and Pseudomonas aeruginosa, with an MIC range of 3.125-6.25 microg/mL. The new 3,4-secotriterpene acid 20-epi-koetjapic acid (5) potently inhibited rat neonatal brain microglia phorbol ester-stimulated thromboxane B(2) (IC(50) = 0.5 microM) and superoxide anion (IC(50) = 1.9 microM) generation.

Bioequivalence evaluation of two brands of cefuroxime 500 mg tablets (Cefuzime and Zinnat) in healthy human volunteers.

A bioequivalence study of two oral formulations of 500 mg cefuroxime axetil was carried out in 24 healthy volunteers following a single dose, standard two-treatment cross-over design at the College of Pharmacy, King Saud University, Riyadh, Saudi Arabia, working jointly with King Khalid University Hospital. The two formulations used were Cefuzime (Julphar, United Arab Emirates) as the test and Zinnat (Glaxo Wellcome, England) as the reference product. Both test and reference tablets were administered to each subject after an overnight fasting on two treatment days separated by a 1-week washout period. After dosing, serial blood samples were collected for a period of 8 h. Plasma harvested from blood was analysed for cefuroxime by a sensitive, reproducible and accurate high pressure liquid chromatography (HPLC) method. Various pharmacokinetic parameters including AUC(0-t), AUC(0-infinity), C(max), T(max), T(1/2) and K(el) were determined from plasma concentrations of both formulations and found to be in good agreement with reported values. AUC(0-t), AUC(0-infinity) and C(max) were tested for bioequivalence after log-transformation of data. No significant difference was found based on an analysis of variance (ANOVA); 90% confidence interval for test/reference ratio of these parameters were found within bioequivalence acceptance range of 80-125%. Based on these statistical inferences, it was concluded that Cefuzime is bioequivalent to Zinnat.

Rhombifoline and 5,6-dehydrolupanine from Anagyrus foetida L.

Rhombifoline and 5,6-dehydrolupanine were isolated for the first time from the leaves and stems of A. foetida L. indigenous to Saudi Arabia. In addition, five other alkaloids, previously identified in A. foetidia L., namely N-methylcytisine, sparteine, anagyrine, lupanine and cytisine, were isolated. The isolated alkaloids were characterized by UV, 1H-NMR, 13C-NMR and Mass spectral data. 13C-NMR data of rhombifoline and 5,6-dehydrolupanine are reported for the first time.

Protective effect of Swertia chirata against indomethacin and other ulcerogenic agent-induced gastric ulcers.

The effect of Swertia chirata has been studied on experimentally induced gastric ulcers in rats. The ethanolic extract of chirata significantly reduced the intensity of gastric mucosal damage induced by indomethacin and necrotizing agents. It produced a significant decrease in gastric secretion in pylorus-ligated rats. The extract inhibited acetylcholine-induced contraction of guinea pig ileum, suggesting its anti-cholinergic activity. Pretreatment of rats with the extract significantly prevented ethanol-induced gastric wall mucus depletion and restored the non-protein sulfhydryl (NP-SH) content in the glandular stomachs. These findings support the use of chirata for the treatment of gastric ulcers in traditional medicine.

Traditional medicinal plants of Saudi Arabia.

The work gives an account of the use of twenty plant species in Saudi traditional medicine and their main chemical constituents. The botanical name, local name or names (in Arabic language), family, mode of administration and voucher herbarium numbers are recorded. Such a study is not only to document the current status of traditional uses of medicinal plants in Saudi Arabia, but also to give awareness of possible new drug resources.

Effect of Salvia haematodes on sexual behaviour of male rats.

The effect of an ethanolic extract of Salvia haematodes roots was studied on the sexual behaviour of male rats. In the initial experiments, male sexual responses were assessed by recording penile erection, licking and grooming of genitals and copulatory movement in absence of females. In the second set, copulatory behaviour was observed by caging males with a receptive female brought into estrus with s.c. injection of estradiol benzoate and progesterone. The frequencies of mounting and intromission and latency of the ejaculation were recorded. The results show that the extract (500 mg/kg, orally) produced a significant increase in episodes of penile erection. The drug was found to enhance the orientation of males towards the female by increased anogenital investigatory behaviour and enhanced licking and grooming of the genitals. The extract also increased the ejaculation latency. These findings support the folk use of this plant as aphrodisiac and for the treatment of premature ejaculation.

Pharmacological studies on aerial parts of Calotropis procera.

The decoction of the aerial part of Calotropis procera is commonly used in Saudi Arabian traditional medicine for the treatment of variety of diseases including fever, joint pain, muscular spasm and constipation. The present investigation was undertaken to confirm its claimed activity in traditional medicine. The ethanol extract of the plant was tested on laboratory animals for its antipyretic, analgesic, anti-inflammatory, antibacterial, purgative and muscle relaxant activities. The results of this study showed a significant antipyretic, analgesic and neuromuscular blocking activity. On smooth muscle of guinea pig ileum, the extract produced contractions which was blocked by atropine supporting its use in constipation. The extract failed to produce significant anti-inflammatory and antibacterial activities. Our phytochemical studies on the aerial parts of C. procera showed the presence of alkaloids, cardiac glycosides, tannins, flavonoids, sterols and/or triterpenes. However, the chemical constituents responsible for the pharmacological activities remains to be investigated. The safety evaluation studies revealed that the use of extract in single high doses (up to 3 g/kg) does not produce any visible toxic symptoms or mortality. However, prolong treatment (90 days) causes significantly higher mortality as compared to control group.

Studies on Ruta chalepensis, an ancient medicinal herb still used in traditional medicine.

An ethanolic extract of the aerial parts of Ruta chalepensis was studied for its anti-inflammatory, antipyretic, analgesic and CNS depressant activities. The extract produced a significant inhibition of carrageenan-induced paw oedema and cotton pellet granuloma in rats. The studies on spontaneous motor activity in mice and conditioned avoidance responding (CAR) in rats showed a dose-dependent depression of the central nervous system in treated animals. Reduction of yeast-induced hyperthermia in mice confirmed its reputed antipyretic activity. The extract did not produce any significant changes in prothrombin time and fibrinogen level. It also failed to produce any analgesic activity in the hot plate reaction-time test in mice. Phytochemical screening of the aerial parts of the plant showed the presence of alkaloids, flavonoids, coumarins, tannins, volatile oil, sterols and/or triterpenes.

Anti-inflammatory activity of Teucrium polium.

Teucrium polium is widely used by the folk-medicine practitioners in Saudi Arabia for the treatment of inflammations, rheumatism, diabetes and ulcers. Scientific reports are lacking to confirm these activities. The present study reports the effect of ethanolic extract of T. polium on carrageenan-induced acute inflammation, cotton-pellet granuloma and some of the biochemical parameters. The ethanolic extract of Teucrium polium at a dose of 500 mg/kg body weight produced significant inhibition of carrageenan-induced inflammation and cotton-pellet granuloma. Biochemical studies showed a significant decrease in glucose level. The presence of flavonoids and sterols might be responsible for the anti-inflammatory activity of this plant. Further studies on the fractionation of the phytoconstituents, and on their mechanism of action are in progress.

Experimental studies on antirheumatic crude drugs used in Saudi traditional medicine.

A large number of herbal drugs are used in the traditional medicine of Saudi Arabia for the treatment of rheumatism, arthritis, gout and other forms of inflammation. In the present study seven of these crude drugs, namely Francoeuria crispa, Hammada elegans, Malus pumila, Ruta chalepensis, Smilax sarsaparilla, Achillea fragrantissima and Alpinia officinarum were tested against carrageenan-induced acute inflammation in rats. The plant materials were extracted with 96% ethanol. The dried extract was dissolved in water for pharmacological testing. The rats were administered an oral dose of 500 mg/kg body weight of each extract 1 h prior to production of inflammation by carrageenan injection (0.05 ml of 1% carrageenan suspension in the planter aponeurosis of the right hind foot). The paw volume was measured at 0,2,3 and 4 h after the injection. Four of the seven plants, namely Francoeuria crispa (24%), Malus pumila (23%), Ruta chalepensis (30%) and Smilax sarsaparilla (25%), produced significant inhibition of carrageenan-induced inflammation in rats. These plants also inhibited cotton pellet-induced exudation. Further studies are suggested to isolate the active principles and for the determination of the mechanism of action of these drugs.

Isolation and identification of an anti-inflammatory principle from Capparis spinosa.

The homologous polyprenols cappaprenol-12 (1), cappaprenol-13 (2) and cappaprenol-14 (3) with 12, 13 and 14 isoprene units, respectively, could be isolated by preparative HPLC from alcoholic extracts of Capparis spinosa. Testing 2 for its anti-inflammatory activity an inhibition of the carrageenan-induced paw edema in rats of 44 vs. 67% for the standard oxyphenbutazone was found.

Post-coital antifertility activity of the seeds of Coriandrum sativum in rats.

Effect of the aqueous extract of fresh coriander (Coriandrum sativum) seeds has been studied on female fertility in rats. Parameters included effects on oestrus cycle, implantation, foetal loss, abortion, teratogenicity and serum progesterone levels on days 5, 12 and 20 of the pregnancy. The extract at doses of 250 and 500 mg/kg orally produced a dose-dependent significant anti-implantation effect, but failed to produce complete infertility. Treatment of animals during day-8 to day-12 and day-12 to day-20 of the pregnancy did not produce any significant abortifacient activity. There was no significant change in the weight and length of the foetuses delivered by rats treated with the extract and no abnormalities were seen in the organs of the offsprings. The extracts produced a significant decrease in serum progesterone levels on day-5 of pregnancy which may be responsible for the anti-implantation effect observed in this study.

Evaluation of mastic, a crude drug obtained from Pistacia lentiscus for gastric and duodenal anti-ulcer activity.

The effect of mastic, a concrete resinous exudate obtained from the stem of the tree Pistacia lentiscus, has been studied on experimentally-induced gastric and duodenal ulcers in rats. Mastic at an oral dose of 500 mg/kg produced a significant reduction in the intensity of gastric mucosal damage induced by pyloric ligation, aspirin, phenylbutazone, reserpine and restraint + cold stress. It produced a significant decrease of free acidity in 6-h pylorus-ligated rats and a marked cytoprotective effect against 50% ethanol in rats which could be reversed by prior treatment with indomethacin. The protective effect was not seen when it was given intraperitoneally in phenylbutazone and restraint + cold stress models. The reduction in the intensity of ulceration in cysteamine-induced duodenal ulcers was not found to be statistically significant in mastic-pretreated rats. The results suggest that mild antisecretory and a localized adaptive cytoprotectant action may be responsible for its anti-ulcer activity. These observations support the results of an earlier study on the clinical effectiveness of mastic in the therapy of duodenal ulcer.