The Chemistry and Bio-Medicinal Significance of Pyrimidines & Condensed Pyrimidines.

This review discusses the biological and medicinal significance of one of the most important and interesting heterocyclic ring systems, the pyrimidine and its condensed derivatives. Herein, various physiologically important molecules, as well as, therapeutically used drugs having a pyrimidine or condensed pyrimidine system in their chemical structures, have been covered. The chemistry and synthesis of pyrimidines have also been briefly discussed.

Docking study of novel antihyperlipidemic thieno[2,3-d]pyrimidine; LM-1554, with some molecular targets related to hyperlipidemia - an investigation into its mechanism of action.

An investigation into the mechanism of antihyperlipidemic action of 2-chloromethyl-5,6,7,8-tetrahydrobenzo(b)thieno[2,3-d]pyrimidin-4(3H)-one (LM-1554) was carried out through docking experiments with six different molecular targets; Niemann Pick C1 Like1 protein (NPC1L1), ATP citrate lyase (ACL), C-reactive protein (CRP), lanosterol 14α-demethylase (LDM), squalene synthase (SqS) and farnesiod X-receptor (FXR) known to be implicated in the physiology of hyperlipidemia. The interactions of LM-1554 were compared with the interactions of their respective co-crystallized native ligands at the active sites of these receptors. These comparisons are based on their docking parameters, as well as, types of interactions and vicinity with various amino acids in the active site pockets.

Some molecular targets for antihyperlipidemic drug research.

High levels of cholesterol and other lipid constituents are major risk factors in the development of atherosclerosis as well as diseases and disorders associated with it. Though, drugs of various categories acting through different mechanisms are available for antihyperlipidemic therapy, there are limitations associated with each of them, keeping the interest in discovery of newer and better antihyperlipidemic drugs alive. Identification and exploitation of novel molecular targets for discovery of new antihyperlipidemic drugs is an important area of research.

In vivo Evaluation of Self Emulsifying Drug Delivery System for Oral Delivery of Nevirapine.

Nevirapine is a highly lipophilic and water insoluble non-nucleoside reverse transcriptase inhibitor used for the treatment of HIV-1 infection. Lymphoid tissue constitutes the major reservoir of HIV virus and infected cells in HIV-infected patients. Self-emulsifying drug delivery system, using long chain triglycerides, is a popular carrier of drugs due to their ability to transport lipophilic drugs into the lymphatic circulation.

Role of lipid-based excipients and their composition on the bioavailability of antiretroviral self-emulsifying formulations.

The objective of this study was to develop self-emulsifying drug delivery system (SEDDS) to improve solubility and enhance the oral absorption of the poorly water-soluble drug, nevirapine. This lipid-based formulation may help to target the drug to lymphoid organs where HIV-1 virus resides mainly. The influence of the oil, surfactant and co-surfactant types on the drug solubility and their ratios on forming efficient and stable SEDDS were investigated in detail.

The chemistry and biological potential of azetidin-2-ones.

Azetidin-2-ones, commonly referred as β-lactams, represent a unique ring system, with interesting chemistry and great biological potential. Besides its well known antibiotic activity, this ring system exhibits a wide range of activities, attracting the attention of researchers. The biological and pharmacological profile of azetidin-2-ones is reviewed here comprehensively with several examples under fourteen different activity heads.

Nose to brain microemulsion-based drug delivery system of rivastigmine: formulation and ex-vivo characterization.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder leading to irreversible loss of neurons, cognition and formation of abnormal protein aggregates. Rivastigmine, a reversible cholinesterase inhibitor used for the treatment of AD, undergoes extensive first-pass metabolism, thus limiting its absolute bioavailability to only 36% after 3-mg dose. Due to extreme aqueous solubility, rivastigmine shows poor penetration and lesser concentration in the brain thus requiring frequent oral dosing.

Investigation of microemulsion system for transdermal delivery of itraconazole.

A new oil-in-water microemulsion-based (ME) gel containing 1% itraconazole (ITZ) was developed for topical delivery. The solubility of ITZ in oils and surfactants was evaluated to identify potential excipients. The microemulsion existence ranges were defined through the construction of the pseudoternary phase diagrams.

Gastroretentive delivery of rifampicin: in vitro mucoadhesion and in vivo gamma scintigraphy.

Rifampicin, a first line anti-tubercular drug, has maximum solubility and permeability in the stomach. An oral multi-particulate formulation with site specific sustained delivery of rifampicin was developed. This oral gastroretentive rifampicin formulation consisted of rifampicin pellets for immediate release as the loading dose and a bio/mucoadhesive rifampicin tablet for extended release.

Push-pull osmotic pump for zero order delivery of lithium carbonate: development and in vitro characterization.

Lithium carbonate, a drug with narrow therapeutic index, needs therapeutic drug monitoring and dose adjustment to maintain lithium level within the therapeutic window. Conventional formulations of lithium carbonate exhibit immediate drug release causing swing/fluctuations in the plasma concentration of lithium, consequently leading to unfavorable side-effects and make dose adjustment difficult. The push-pull osmotic pump has been developed for zero order delivery of lithium carbonate for a period of 24 h.

Pharmacokinetic Study of a Novel Antihyperlipidemic Agent LM-13765- A Prodrug.

A sensitive and specific high performance thin layer chromatographic method has been developed for estimation of a novel antihyperlipidemic agent LM 13765 in rabbit plasma and its use for pharmacokinetic study has been evaluated. The proposed method was employed to study pharmacokinetics of LM 13765 in rabbits. It was observed that LM 13765 metabolized immediately after oral administration.

Multivariate optimization of formulation and process variables influencing physico-mechanical characteristics of site-specific release isoniazid pellets.

In the present study, isoniazid was formulated as site-specific release pellets with high drug loading (65%, w/w) using extrusion-spheronization followed by aqueous coating of Sureteric (35% weight gain). A statistical experimental strategy was developed to optimize simultaneously the effect of the two formulation variables and one process variable on the critical physico-mechanical properties of the core pellets of isoniazid. Amount of granulating fluid and amount of binder were selected as formulation variables and spheronization speed as a process variable.

Design, synthesis and pharmacological evaluation of a series of 5-carbethoxy-4-chloro-6-(substituted amino)pyrimidines as potential analgesic and anti-flammatory agents with very low ulcerogenic potential.

A series of 5-carbethoxy-4-chloro-6-(substituted amino)pyrimidines was designed on the basis of its good 3-dimensional structural similarity with mefenamic acid (CAS 61-68-7), a well known anti-inflammatory drug. Synthesis of some 5-carbethoxy-4-chloro-6-(substitutedamino)pyrimidines has been achieved by cyclization of N-(cyanovinyl)formamidine intermediate in the presence of dry HCl. Target compounds were evaluated for their analgesic and anti-inflammatory potential by known experimental models.

Synthesis of novel bioactive derivatives of 3-(4-chlorophenyl)-2-hydrazino-5,6,7,8-tetrahydrobenzo(b)thieno[2,3-d]pyrimidine-4(3H)-ones.

A series of triazolo[4,3-a]tetrahydrobenzo(b)thieno[3,2-e]pyrimidine-5(4H)-ones (12a-n) were synthesized and evaluated for CNS depressant, skeletal muscle relaxant and anticonvulsant activities by photoactometer, Rotarod and pentylenetetrazole induced the convulsions method respectively in Swiss albino mice. Diazepam was used as standard drug. The five derivatives 12b, 12c, 12d, 12i and 12m showed the CNS depressant and skeletal muscle relaxant activities comparable to those of diazepam at a dose of 5mg/kg.

Dissolution test for site-specific release isoniazid pellets in USP apparatus 3 (reciprocating cylinder): optimization using response surface methodology.

The present work aims to predict drug release from novel site-specific release isoniazid pellets, in USP dissolution test apparatus 3, using the response surface methodology (RSM). Site-specific release isoniazid pellets were prepared by extrusion-spheronization followed by aqueous coating of Acryl-EZE. RSM was employed for designing of the experiment, generation of mathematical models and optimization study.

Synthesis and antihyperlipidemic activity of some novel condensed 2-chloroalkyl-4-chloro/hydroxy-5,6-disubstituted pyrimidines.

Synthesis and antihyperlipidemic activity of a series of novel condensed 2-chloroalkyl-4-chloro/hydroxy-5,6-di-substituted pyrimidines are described. The design of these compounds is based on the earlier QSAR study on the antihyperlipidemic 2-substituted methylthienopyrimidin-4-ones. The newly synthesized condensed 4-chloro-2-chloroalkylpyrimidines (IIIa-n) have exhibited much superior antihyperlipidemic activity, compared to their earlier reported 4-hydroxy analogs.

The biology and chemistry of hyperlipidemia.

Coronary arterial diseases are responsible for more deaths than all other associated causes combined. Elevated serum cholesterol levels leading to atherosclerosis can cause coronary heart disease (CHD). Reduction in serum cholesterol levels reduces the risk for CHD, substantially.

Impaired bioavailability of rifampicin in presence of isoniazid from fixed dose combination (FDC) formulation.

The present study describes comparative bioavailability of rifampicin (RIF) after administration of a single component RIF (450 mg) capsule and rifampicin-isoniazid (RIF-INH) (450+300 mg) fixed dose combination (FDC) capsule formulations. Six healthy male volunteers participated in a single dose, two treatment, two period, cross-over study. A sensitive, specific and accurate HPTLC method was developed, validated and employed for estimation of RIF and its major active metabolite, 25-Desacetylrifampicin (25-DAR) levels, in urine.

Design, synthesis and antihistaminic (H1)activity of some condensed 2-(substituted)arylaminoethylpyrimidin-4(3H)-ones.

The synthesis and potential H1 receptor antagonistic activity of two novel series of condensed 2-arylaminoethylpyrimidin-4(3H)-ones (4, 5) and 4-amino-2-arylaminoethyl pyrimidines (6) have been reported. All the novel compounds were found to antagonize histamine in a competitive and reversible manner. When tested on guinea-pig ileum, compounds exhibited H1-antagonistic activity, (pA2 values) in the range of 8.

Estimation of individual sennosides in plant materials and marketed formulations by an HPTLC method.

Senna is a well-known drug, used in the Ayurvedic and Allopathic systems of medicine, and is a treatment for constipation. The purgative action of senna and its formulations is due to the presence of sennosides A and B. An HPTLC method has been developed for the determination of individual sennosides (A, B, C, D) without any derivatization in marketed formulations (three tablet formulations, two granule formulations and one liquid formulation) and plant materials (senna leaf and pod).

Design, synthesis and antihistaminic (H(1)) activity of some condensed 3-aminopyrimidin-4(3H)-ones.

Anovel series of condensed 3-amino-2-(substituted)methylpyrimidin-4(3H)-ones is reported with potential H(1) receptor antagonistic activity. The IC(50) values for 23 compounds were found to be in the micromolar range. Five lead compounds (10c, e, g, r and t), when evaluated by the in vivo method were found to protect guinea-pigs from the histamine induced asphyxia and antagonized histamine in a competitive and reversible manner.

Stability of rifampicin in dissolution medium in presence of isoniazid.

Rifampicin (RIF) hydrolyzes in acidic medium to form insoluble and poorly absorbed 3-Formyl rifamycin SV (3-FRSV). This study describes development of two principally different methods, Dual Wavelength UV-Vis. spectrophotometry (DW spectrophotometry) and HPTLC, to determine 3-FRSV in presence of RIF.

Mechanism of the antihyperlipaemic activity and pharmacokinetics of 2-chloromethyl-5,6,7,8-tetrahydrobenzo(b)thieno[2,3-d]pyrimidin-4(3H)-o ne.

The pharmacokinetics and the mechanism of action of the antihyperlipaemic compound 2-chloromethyl-5,6,7,8-tetrahydrobenzo(b)thieno[2,3-d]pyrimidin-4(3H)-on e (CAS 89587-03-3, LM-1554) have been studied. Serum concentrations were determined by reverse phase HPLC using methanol : water (60 : 40) as the solvent system. The results of pharmacokinetic studies suggest that the compound LM-1554 is poorly absorbed from the gastrointestinal tract after the oral administration in dogs and rabbits.

Synthesis and evaluation of 2-chloromethyl-3-N-substituted arylthieno (2,3-d)pyrimidin-4-ones and derivatives for central nervous system depressant activity.

2-Chloromethyl 3-N-substituted arylthieno (2,3-d)pyrimidin-4-ones and derivatives were synthesized by reacting 2-amino-3-carboxanilido-4,5,6,7-tetrahydrobenzo(b)thiophenes (Iabc) with chloroacetyl chloride in dioxane and by cyclizing the open chain 3-substituted carboxanilido-2-(omega-chloroacetamido)-4,5,6,7-tetrahydrobe nzo(b)thiophenes (IIabc) under acidic condition. The compounds were characterized by their spectral data and screened for central nervous system depressant activity. The compounds IIIabc and Vabc have shown marked sedative action.

Synthesis and QSAR of some 3-amino-2-(substituted)aminomethyl-5,6-disubstituted thieno[2,3-d]pyrimidin-4(3H)-ones as novel H1-receptor antagonists.

The present study describes the synthesis and quantitative structure activity relationships (QSAR) of novel 3-amino-2-(substituted)aminomethyl-5,6-disubstitutedthieno[2,3-d] pyrimidin-4(3H)-ones for their potent H1-receptor antagonist activity on the guinea pig ileum. With the IC50 values in the range of 10(-5) gms/lit, all the compounds tested were found to possess ten fold higher affinity to the H1-receptor than diphenhydramine and cetirizine, but lower than astemizole and loratidine. The sedative potential of these compounds was found to be lower than cetirizine and astemizole but comparable to loratidine.