Chromatographic fractionation of the alcoholic extract of leaves of Punica granatum L. var. nana (Punicaceae) resulted in the isolation and identification of nine compounds, three of them are firstly reported in the family: β-amyrin (1), corosolic acid (4) and luteolin-7-O-(6``-O-galloyl)-β-D-glucoside (9) in addition to β-sitosterol (2), ursolic acid (3), friedelin (5), β-sitosterol-3-O-β-D-glucopyranoside (6), 2-methyl-pyran-4-one-3-O-β-D-glucopyranosid (7), luteolin-4'-O-β-D-glucoside (8). Their structures were established by various spectroscopic methods (1H NMR, 13C NMR, HSQC, HMBC and UV spectroscopy) as well as comparison with authentic samples. Biological studies of different extracts of P. granatum L. var. nana (ornamental pomegranate) in comparison with P. granatum L. (edible pomegranate) showed that the extracts of edible pomegranate have slightly higher antioxidant activity than the corresponding extracts of the ornamental one using DPPH assay, while the extracts of ornamental pomegranate have higher anti-inflammatory activity than corresponding extracts of the edible one using carrageenan-induced rat hind paw edema model.

Abstract A series of identical twin esters 3a-e of metronidazole was synthesized and evaluated as potential prodrugs with improved physicochemical and pharmacokinetic properties. The synthesis of the twin esters 3a-e was achieved by interaction of metronidazole with the respective dicarboxylic acid anhydride or their dichloride. Their structures were verified by elemental and spectroscopic analyses. The lipophilicity of metronidazole and the prodrugs 3a-e, expressed as Rmvalues, were determined using reversed-phase TLC and revealed enhanced lipophilic properties compared with metronidazole. Reversion kinetics of the parent drug from its twin esters was investigated in aqueous buffer solutions (pH 1.2 and 7.4) as well as in biological media (80% human plasma and 20 % rat liver homogenate) at 37 °C using HPLC. In all cases, the hydrolysis followed pseudo-first-order kinetics in a two-step reaction (k1 and k2) via the intermediate formation of the respective metronidazole hemiester. All the synthesized twin ester prodrugs 3a-e were proved to be chemically stable at acidic pH (t1/2 ~ 25–72 h) and also at the physiological pH (t1/2 ~ 13–40 h). Meanwhile, the release of the first molecule of metronidazole from its twin esters 3a-d ensued rapidly in 80% human plasma (t1/2 ~ 10–150 min) and in rat liver homogenate (t1/2 ~ 4–55 min). The resulting hemiesters 2a-d showed a sustained release of the second molecule in the same biological fluids (t1/2 ~ 3–9 h and 1–11 h respectively). In vivo evaluation studies of metronidazole and its twin esters 3a-d in mice and 3b in rabbits revealed that the prodrugs have been absorbed almost unhydrolyzed with considerable higher plasma level. Antiparasitic activity of the synthesized compounds was evaluated in mice against Giardia muris, the prodrug 3b showed improved antigiardial activity compared to the parent drug. These results suggest that the synthesized identical twin esters 3a-d may be useful as a promising new prodrug form of metronidazole for oral drug delivery.

Abstract A series of identical twin esters 3a-e of metronidazole was synthesized and evaluated as potential prodrugs with improved physicochemical and pharmacokinetic properties. The synthesis of the twin esters 3a-e was achieved by interaction of metronidazole with the respective dicarboxylic acid anhydride or their dichloride. Their structures were verified by elemental and spectroscopic analyses. The lipophilicity of metronidazole and the prodrugs 3a-e, expressed as Rmvalues, were determined using reversed-phase TLC and revealed enhanced lipophilic properties compared with metronidazole. Reversion kinetics of the parent drug from its twin esters was investigated in aqueous buffer solutions (pH 1.2 and 7.4) as well as in biological media (80% human plasma and 20 % rat liver homogenate) at 37 °C using HPLC. In all cases, the hydrolysis followed pseudo-first-order kinetics in a two-step reaction (k1 and k2) via the intermediate formation of the respective metronidazole hemiester. All the synthesized twin ester prodrugs 3a-e were proved to be chemically stable at acidic pH (t1/2 ~ 25–72 h) and also at the physiological pH (t1/2 ~ 13–40 h). Meanwhile, the release of the first molecule of metronidazole from its twin esters 3a-d ensued rapidly in 80% human plasma (t1/2 ~ 10–150 min) and in rat liver homogenate (t1/2 ~ 4–55 min). The resulting hemiesters 2a-d showed a sustained release of the second molecule in the same biological fluids (t1/2 ~ 3–9 h and 1–11 h respectively). In vivo evaluation studies of metronidazole and its twin esters 3a-d in mice and 3b in rabbits revealed that the prodrugs have been absorbed almost unhydrolyzed with considerable higher plasma level. Antiparasitic activity of the synthesized compounds was evaluated in mice against Giardia muris, the prodrug 3b showed improved antigiardial activity compared to the parent drug. These results suggest that the synthesized identical twin esters 3a-d may be useful as a promising new prodrug form of metronidazole for oral drug delivery.

Abstract A series of identical twin esters 3a-e of metronidazole was synthesized and evaluated as potential prodrugs with improved physicochemical and pharmacokinetic properties. The synthesis of the twin esters 3a-e was achieved by interaction of metronidazole with the respective dicarboxylic acid anhydride or their dichloride. Their structures were verified by elemental and spectroscopic analyses. The lipophilicity of metronidazole and the prodrugs 3a-e, expressed as Rmvalues, were determined using reversed-phase TLC and revealed enhanced lipophilic properties compared with metronidazole. Reversion kinetics of the parent drug from its twin esters was investigated in aqueous buffer solutions (pH 1.2 and 7.4) as well as in biological media (80% human plasma and 20 % rat liver homogenate) at 37 °C using HPLC. In all cases, the hydrolysis followed pseudo-first-order kinetics in a two-step reaction (k1 and k2) via the intermediate formation of the respective metronidazole hemiester. All the synthesized twin ester prodrugs 3a-e were proved to be chemically stable at acidic pH (t1/2 ~ 25–72 h) and also at the physiological pH (t1/2 ~ 13–40 h). Meanwhile, the release of the first molecule of metronidazole from its twin esters 3a-d ensued rapidly in 80% human plasma (t1/2 ~ 10–150 min) and in rat liver homogenate (t1/2 ~ 4–55 min). The resulting hemiesters 2a-d showed a sustained release of the second molecule in the same biological fluids (t1/2 ~ 3–9 h and 1–11 h respectively). In vivo evaluation studies of metronidazole and its twin esters 3a-d in mice and 3b in rabbits revealed that the prodrugs have been absorbed almost unhydrolyzed with considerable higher plasma level. Antiparasitic activity of the synthesized compounds was evaluated in mice against Giardia muris, the prodrug 3b showed improved antigiardial activity compared to the parent drug. These results suggest that the synthesized identical twin esters 3a-d may be useful as a promising new prodrug form of metronidazole for oral drug delivery.

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Bioassay guided fractionation of the roots of Lantana montevidensis (Verbenaceae) has resulted in the isolation and identification of three new triterpenoids; 13-hydroxy-3-oxo-olean-11-en-28-oic acid (1), 12,13-dihydroxyolean-3-oxo-28-oic acid (2) and 12,13,22-trihydroxyolean-3-oxo-28-oic acid (3) in addition to nine known compounds: oleanonic acid (4), oleanolic acid (5), 3,25-dihydroxy-olean-12-en-28-oic acid (6), lantadene A (7), 19-hydroxy-3-oxo-olean-12-en-28-oic acid (8) pomolic acid (9), camaric acid (10) together with -sitosterol (11) and -sitosterol-3-O--D-glucoside (12). The structures of the isolated metabolites were elucidated based on comprehensive 1D and 2D NMR spectroscopic data as well as HR-ESI–MS. The extracts and the isolated metabolites were evaluated for their antiprotozoal and antimicrobial activities. Compound 2 showed antibacterial activity against Staphylococcus aureus and methicillin resistant S. aureus with IC50 values against both organisms of 2.1 µM and compound 10 showed activity against same organisms with IC50 values 8.74 and 8.09 µM, respectively, compared to the positive control ciprofloxacin (IC50 = 0.3 µM against S. aureus and MRSA). Compounds 1, 4, 5, 6, and 10 showed moderate antileishmanial activity with IC50 values ranging between (2.54–14.95 µM) and IC90 values ranging between (11.90–19.47 µM), using pentamidine as a control (IC50 values 2.09  16.8 µM) and IC90 values ranging between (4.72  16.8 µM). These compounds also showed highly potent antitrypanosomal activity with IC50 values ranging between (0.39–7.12 µM) and IC90 values ranging between (1.91–10.51 µM), which are more efficient than the DFMO, the antitrypanosomal drug employed as positive control (IC50 and IC90 values 11.82 and 30.82 µM).

Bioassay guided fractionation of the roots of Lantana montevidensis (Verbenaceae) has resulted in the isolation and identification of three new triterpenoids; 13-hydroxy-3-oxo-olean-11-en-28-oic acid (1), 12,13-dihydroxyolean-3-oxo-28-oic acid (2) and 12,13,22-trihydroxyolean-3-oxo-28-oic acid (3) in addition to nine known compounds: oleanonic acid (4), oleanolic acid (5), 3,25-dihydroxy-olean-12-en-28-oic acid (6), lantadene A (7), 19-hydroxy-3-oxo-olean-12-en-28-oic acid (8) pomolic acid (9), camaric acid (10) together with -sitosterol (11) and -sitosterol-3-O--D-glucoside (12). The structures of the isolated metabolites were elucidated based on comprehensive 1D and 2D NMR spectroscopic data as well as HR-ESI–MS. The extracts and the isolated metabolites were evaluated for their antiprotozoal and antimicrobial activities. Compound 2 showed antibacterial activity against Staphylococcus aureus and methicillin resistant S. aureus with IC50 values against both organisms of 2.1 µM and compound 10 showed activity against same organisms with IC50 values 8.74 and 8.09 µM, respectively, compared to the positive control ciprofloxacin (IC50 = 0.3 µM against S. aureus and MRSA). Compounds 1, 4, 5, 6, and 10 showed moderate antileishmanial activity with IC50 values ranging between (2.54–14.95 µM) and IC90 values ranging between (11.90–19.47 µM), using pentamidine as a control (IC50 values 2.09  16.8 µM) and IC90 values ranging between (4.72  16.8 µM). These compounds also showed highly potent antitrypanosomal activity with IC50 values ranging between (0.39–7.12 µM) and IC90 values ranging between (1.91–10.51 µM), which are more efficient than the DFMO, the antitrypanosomal drug employed as positive control (IC50 and IC90 values 11.82 and 30.82 µM).

Bioassay guided fractionation of the roots of Lantana montevidensis (Verbenaceae) has resulted in the isolation and identification of three new triterpenoids; 13-hydroxy-3-oxo-olean-11-en-28-oic acid (1), 12,13-dihydroxyolean-3-oxo-28-oic acid (2) and 12,13,22-trihydroxyolean-3-oxo-28-oic acid (3) in addition to nine known compounds: oleanonic acid (4), oleanolic acid (5), 3,25-dihydroxy-olean-12-en-28-oic acid (6), lantadene A (7), 19-hydroxy-3-oxo-olean-12-en-28-oic acid (8) pomolic acid (9), camaric acid (10) together with -sitosterol (11) and -sitosterol-3-O--D-glucoside (12). The structures of the isolated metabolites were elucidated based on comprehensive 1D and 2D NMR spectroscopic data as well as HR-ESI–MS. The extracts and the isolated metabolites were evaluated for their antiprotozoal and antimicrobial activities. Compound 2 showed antibacterial activity against Staphylococcus aureus and methicillin resistant S. aureus with IC50 values against both organisms of 2.1 µM and compound 10 showed activity against same organisms with IC50 values 8.74 and 8.09 µM, respectively, compared to the positive control ciprofloxacin (IC50 = 0.3 µM against S. aureus and MRSA). Compounds 1, 4, 5, 6, and 10 showed moderate antileishmanial activity with IC50 values ranging between (2.54–14.95 µM) and IC90 values ranging between (11.90–19.47 µM), using pentamidine as a control (IC50 values 2.09  16.8 µM) and IC90 values ranging between (4.72  16.8 µM). These compounds also showed highly potent antitrypanosomal activity with IC50 values ranging between (0.39–7.12 µM) and IC90 values ranging between (1.91–10.51 µM), which are more efficient than the DFMO, the antitrypanosomal drug employed as positive control (IC50 and IC90 values 11.82 and 30.82 µM).