Medicinal Chemistry

In regards to patient compliance for drug delivery, oral drug delivery is generally the preferred route of administration. However, parental injection of peptide drugs has always been the primary method of peptide drug administration. This is a result of the poor oral bioavailability of peptide drugs, which are typically under 1%. The degradation of peptides in the gastrointestinal (GI) tract by peptidase enzymes and harsh pH, combined with the poor intestinal mucosal penetration properties of the non-drug-like peptide drugs have been identified as the major barriers towards improving the oral bioavailability. Nevertheless, oral delivery of peptide drug presents a significant challenge due to the enzymatic degradation by enzymes in the GI tract and the poor penetration of the peptides across gastro-intestinal epithelium membranes, particularly for adults. Therefore, a novel peptide drug analogue or pro-drug that both protect peptide drugs from degradation by the enzymes in the GI tract that also improves its penetration across the intestinal epithelium membrane would greatly advance the development of peptide drugs as effective candidates for the treatment of various diseases. So far several approaches are being investigated to improve the oral bioavailability of peptide drugs by different researchers. Indications suggest that chemical modification such as incorporation of unnatural amino acids, unnatural peptide bonds, cyclisation and pro-drug approaches as well as nanoparticulates systems such as nanoparticles and microemulsions offer great potential for improvement and likelihood of enabling peptide drug to be administered orally. This review will focus on the chemical modification methods and other approaches (such as using variable nanoparticular delivery systems), that could be used to overcome the barriers involved in low oral bioavailability of peptide drugs.

A novel reversed-phase liquid chromatographic method with UV detection for rapid and accurate simultaneous quantitation of prazosin (PRZ) and the key calcium channel blockers (CCBS), amlodipine besylate (AML), diltiazem hydrochloride (DIL) and verapamil hydrochloride (VER) in active pharmaceutical ingredients, pharmaceutical dosage formulations and human serum has been developed and validated according to ICH guidelines.

The reduced run time and low cost of analysis are additional merits of the method. This method showed the best resolution by using pre-packed Nucleosil® C18 (10 μm, 25 × 0.46 cm) column at ambient temperature. The mobile phase consisting of methanol:water:acetonitrile (55:35:10 v/v; pH adjusted to 2.65 with phosphoric acid) was pumped at a flow rate of 1.0 mL min-1 with an average operating pressure of 130 kg/cm2 and effluent was monitored at 238 nm. Linearity of the method in the concentration range 5-100 μg mL-1 for prazosin and 10-600 μg mL-1 for calcium channel blockers showed good linear relationships for all the analytes (R2 < 0.9998). The LLOD values were 32.8, 30.6, 54.2, 29.9 and LLOQ were 99.4, 92.6, 164.2, 90.5 ng mL-1 for PRZ, AML, DIL and VER respectively, as per ICH guide lines acceptance criteria of 98 - 102%.

The newly developed method has been successfully employed for studying the interactions between prazosin and ca-channel blockers at simulated human body conditions; the results envisage a positive interaction between the two classes of drugs, as the percent recovery of the drugs almost changed, which indicate that prazosin may not be safe to co-administer with these antihypertensive drugs

Structurally morpholine containing Cinnamamide derivatives have been synthesized in quantitative yields by the reaction of different substituted cinnamicacids with morpholine. The structures of the newly synthesized compounds were confirmed by their IR, LC-MS, 1H & 13C-NMR spectral data. The synthesized compounds were evaluated for their antimicrobial activity against bacterial species Bacillus subtilis and Escherichia coli etc and in vitro antioxidant activity by employing DPPH, hydrogen peroxide, and nitric oxide radical scavenging assays. Among these prepared compounds 4i and 4j showed significant antioxidant, antibacterial as well as antifungal activity and these were found to be the most potent activity molecules when compared with that of standard drugs.

Sericulture is a traditional and well-known industry with a 5000-year history in China. ‘Byproducts of sericulture’ which do not directly generate economic benefits, are typically wasted: e.g., fruits, stems, surplus leaves from silkworm feeding, pupae and moths. However, the above resource is of great potential nutritional and medicinal value and deserves systematic and profound study.

Bcr-Abl-T315I mutation-induced imatinib (IM) resistance remains a major challenge for clinical management of chronic myelogenous leukemia (CML). Therefore it is imperative to search for novel agents to overcome IMresistance. 2-Tert-butyl-1,4-benzoquinone (TBQ) is an oxidation product of 2-tert-Butylhydroquinone (TBHQ) which has been developed as a food additive and proves to be a strong antioxidant. Previous studies showed that TBQ has cytotoxic effect on different types of neoplastic cells. Our recent study confirmed that TBQ induced apoptosis and cell proliferation inhibition in CML cells and inhibited the growth of IM-resistant primary monocytes from CML patients. Here we further report that TBQ-induced caspase activation is required for the downregulation of Bcr-Abl and apoptotic cell death in both IM-resistant and IM-sensitive CML cells. These findings suggest an alternative strategy to overcome IM resistance by enhancing Bcr-Abl downregulation with TBQ.

Type 2 diabetes mellitus is a complex disease and a global health problem; hence the first level of health care should handle the approaches of medical genetics to reduce its incidence. In this manuscript we present perspectives of the study of genomic medicine carried out in Mexican population, which show a molecular heterogeneity according to the studied population. Genes currently associated to diabetes are fifty, including ABCA1, APOE, BGLAP, LRP2, CYP19A1, hIAPP, SCARB1, TCF7L2, TNFA. Up to date there are no variants related to diabetes mellitus in the HNF1β, INS, and NEUROD1 among other genes. In relation to chronic complications of DM2, the genes ACE, ADRB3, APOE, CUBN, hANP, LRP2 and HPSE are analyzed.

A kinetic analysis of intramolecular oxidation reactions of 1 derivatives in combination with the published data on antimalarial activity makes it possible to formulate the following mechanism of action of the peroxide drugs, analogs of compound 1. Under the reaction of the Fe(II) chelates the compound containing the peroxide group is transformed into the alkoxyl radical. This radical isomerizes to the alkyl radical, which further undergoes intramolecular chain oxidation. This oxidation results in polyatomic hydroperoxides, which, in turn, generates radicals in the reaction with Fe(II). The next cascade of radical reactions generates very reactive hydroxyl radicals, whose sources are peroxyl radicals with hydroperoxide fragments and α-dihydroperoxides. The higher the yield of hydroxyl radicals nOH, the more efficient the drug. The dependence of the antimalarial activity of the ith drug IC50(1)M(i)/ IC50(i)M(1) on the yield of radicals HO nOH is nonlin ear (exponential). The compounds with nOH 3 are efficient.

A novel series of 2-thioxoimidazolidin-4-one and Benzothiazole thioglycosides were synthesized via one-pot reaction of the 2-thioxoimidazolidin-4-one and Benzothiazole thiolate salts, respectively with 2,3,4,6-tetra-O-acetyl- α-D-gluco- and galactopyranosyl bromides. The cytotoxic activity of compound 7, 8a, 8b, 10a, 10b, 15a and 15b were evaluated against MCF-7 cell lines (Breast carcinoma cell lines) showing high to moderate anti-tumor activities moreover molecular modeling of these compounds revealed that they have high binding affinity through hydrophobichydrophobic interaction and moderate selectivity through the hydrogen bond interaction with the atypical nucleotide binding pocket in the amino terminus of HSP90.