Preclinical pharmacokinetics and bioavailability of noscapine, a tubulin-binding anticancer agent.

BACKGROUND: Noscapine, a naturally occurring antitussive phthalideisoquinoline alkaloid, is a tubulin-binding agent currently in Phase I/II clinical trials for anticancer therapy. Unlike currently available antimitotics such as taxanes and vincas, noscapine is water-soluble, well tolerated, and shows no detectable toxicity. OBJECTIVE: The goal was to develop a simple, sensitive, quantitative, selective, and less time-consuming high-performance liquid chromatography (HPLC) method for determination of noscapine and to study its pharmacokinetics in mice models. METHOD: Noscapine was extracted from mice plasma using the protein-precipitation method and detected using a reversed-phase C8 column with mobile phase consisting of 35% acetonitrile and 65% ammonium acetate buffer (pH 4.5) at 232 nm wavelength. Pharmacokinetic studies of noscapine were performed in mice following intravenous bolus at 10 mg/kg and oral administrations at 75, 150, and 300 mg/kg. RESULTS: The standard curves for noscapine estimation were linear between 390 and 50,000 ng/ml (lower limit of quantification was 390 ng/ml) and the recovery was approximately 80%. Following 10 mg/kg intravenous dose, mean plasma concentrations of 7.88 microg/ml were achieved at 5 min in mice and declined with undetectable levels at 4 h. The mean total body clearance was 4.78 l/h. The mean volume of distribution (V (d)) was 5.05 l. Non-compartmental analysis yielded the mean area under the plasma concentration-time curve (AUC) for noscapine as 53.42, 64.08, and 198.35 h microg/ml reaching maximum plasma concentrations (C (max)) of 12.74, 23.24, and 46.73 microg/ml at a t (max) of 1.12, 1.50, and 0.46 h at the linearly increasing dose levels. CONCLUSION: A rapid and simple HPLC/UV method for the quantification of noscapine in plasma has been developed to study pharmacokinetics of noscapine at tumor-suppressive doses in the mouse. Since orally available anticancer drugs are rare, therefore, noscapine, an innocuous agent, having a mean oral bioavailability of 31.5% over the studied dose range merits its further advancement in humans for anticancer therapy.

Synthesis of 1-[3-(4-benzotriazol-1/2-yl-3-fluoro-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-3-substituted-thiourea derivatives as antituberculosis agents.

In continuation of our research program for new antituberculosis drugs, we have designed, synthesized and evaluated antimycobacterial activity of new series of 1-[3-(4-benzotriazol-1/2-yl-3-fluoro-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-3-substituted-thiourea derivatives against different Mycobacterium species i.e. M. tuberculosis, M. avium and M. intracellulare in an agar dilution method. Compound 17 exhibited excellent antimycobacterial activity (in vitro) against drug sensitive and resistant clinical isolates of M. tuberculosis. Its MIC value is equivalent to linezolid and superior to isoniazid against all these strains.

Anti-tubercular agents. Part 3. Benzothiadiazine as a novel scaffold for anti-Mycobacterium activity.

In an effort to develop new and more effective therapies to treat tuberculosis, a series of benzothiadiazine 1,1-dioxide derivatives were synthesized and their in vitro activity against Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium intracellulare was evaluated. One of the compounds, 8c, exhibited potent anti-tubercular activity, particularly for the resistant strains and thus prompted us to investigate its in vivo profile. However, the in vivo testing in a mouse model of tuberculosis infection did not show significant anti-tubercular activity, probably because of its poor bioavailability.

Complete 1H and 13C NMR assignments of six saponins from Sapindus trifoliatus.

Complete 1H and 13C spectral assignments are reported for six saponins from the pericarp of Sapindus trifoliatus (Hindi name: Reetha) collected from Madhya Pradesh and Maharashtra, India, using only 1D and 2D NMR methods. The structures of the compounds were elucidated as hederagenin 3-O-(3-O-acetyl-beta-D-xylopyranosyl)-(1-3)-alpha-L-rhamnopyranosyl-(1-2)-alpha-L-ara-binopyranoside, hederagenin 3-O-(4-O-acetyl-beta-D-xylop-yranosyl)-(1-3)-alpha-L-rhamnopyranosyl-(1-2)-alpha-L-arabinop-yranoside, hederagenin 3-O-(3,4-O-diacetyl-beta-D-xylopy-ranosyl)-(1-3)-alpha-L-rhamnopyranosyl-(1-2)-alpha-L-arabinopy-ranoside, hederagenin 3-O-(3,4-O-diacetyl-alpha-L-arabinop-yranosyl)-(1-3)-alpha-L-rhamnopyranosyl-(1-2)-alpha-L-arabinop-yranoside, hederagenin 3-O-(beta-D-xylopyranosyl)-(1-3)-alpha-L-rhamnopyranosyl-(1-2)-alpha-L-arabinopyranoside and he-deragenin 3-O-(alpha-L-arabinopyranosyl)-(1-3)-alpha-L-rhamno-pyranosyl-(1-2)-alpha-L-arabinopyranoside. It is concluded that saponins of this complexity approach the limit of structural complexity, which can be solved by NMR alone, precisely and quickly.

Synthesis of some diguanidino 1-methyl-2,5-diaryl-1H-pyrroles as antifungal agents.

A series of novel 2,5-bis(guanidino-aryl)-1-methyl-1H-pyrroles 9a-h has been synthesized starting from 1-methyl-1H-pyrrole. The antifungal activities of compounds were evaluated by in vitro agar diffusion and broth dilution assay against Candida spp. and Aspergillus spp. Compound 9c from this series was found to be equipotent or more potent than fluconazole, whereas compound 9d was comparable to fluconazole against most of the tested strains.

Synthesis and antibacterial activity of novel (un)substituted benzotriazolyl oxazolidinone derivatives.

A series of novel (un)substituted benzotriazolyl oxazolidinone derivatives has been synthesized and tested for in vitro antibacterial activities by MIC determination against a panel of susceptible and resistant Gram-positive and Gram-negative microorganisms, some of which are resistant to methicillin and vancomycin. Compounds 20, 21, 24, 29 and 30 from this series were found to be equipotent or more potent than linezolid in vitro.

Synthesis of isonicotinic acid N'-arylidene-N-[2-oxo-2-(4-aryl-piperazin-1-yl)-ethyl]-hydrazides as antituberculosis agents.

A new series of antituberculosis agents 6-9 was designed, synthesized and evaluated for antituberculosis activity against Mycobacterium tuberculosis H37Rv and clinical isolates in an agar dilution method. Compound 9h showed comparable in vitro activity (MIC) to isoniazid against M. tuberculosis H37Rv and clinical isolates (sensitive strains) and superior activity against resistant strains of M. tuberculosis.

Synthesis of novel substituted tetrazoles having antifungal activity.

In an effort to find potent antifungal agents, a variety of triazole derivatives with a 5-substituted tetrazole structure 6, 7, 12 and 14 were prepared and evaluated for antifungal activity against Candida spp., Cryptococcus neoformans, and Aspergillus spp. in vitro. The location of the methyl group at the C-3 of compounds 12 and 14 has been demonstrated to be a key structural element of antifungal potency.

Optically active antifungal azoles: synthesis and antifungal activity of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-[2-[4-aryl-piperazin-1-yl]-ethyl]-tetrazol-2-yl/1-yl)-1-[1,2,4]-triazol-1-yl-butan-2-ol.

A series of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-[2-[4-aryl-piperazin-1-yl]-ethyl]-tetrazol-2-yl)-1-[1,2,4]-triazol-1-yl-butan-2-ol (11a-n) and (2R,3S)-2-(2,4-difluorophenyl)-3-(5-[2-[4-aryl-piperazin-1-yl]-ethyl]-tetrazole-1-yl)-1-[1,2,4]-triazol-1-yl-butan-2-ol (12a-n) has been synthesized. The antifungal activity of compounds was evaluated by in vitro agar diffusion and broth dilution assay. Compounds 11d and its positional isomer 12d having 3-trifluoromethyl substitution on the phenyl ring of piperazine demonstrated significant antifungal activity against variety of fungal cultures (Candida spp. C. neoformans and Aspergillus spp.). The compound 12d showed MIC value of 0.12 microg/mL for C. albicans, C. albicans V-01-191A-261 (resistant strain); 0.25 microg/mL for C. tropicalis, C. parapsilosis ATCC 22019 and C. krusei and MIC value of 0.5 microg/mL for C. glabrata, C. krusei ATCC 6258, which is comparable to itraconazole and better than fluconazole. Further, compound 11d showed significant activity (MIC; 0.25-0.5 microg/mL) against Candida spp. and strong anticryptococcal activity (MIC; 0.25 microg/mL) against C. neoformans.