Medicinal Chemistry - Volume 6, Issue 2, 2010

Three derivatives of ciprofloxacin (compound B, C, and D) were constructed utilizing microwave synthesis methodology (compound D) or diazoalkane reaction in nonaqueous solvent (compounds B and C). The final structures of the derivatives featured an ester group in place of the original carboxyl group of the ciprofloxacin. These ester groups contained aliphatic single carbon (compound B), two carbon length (compound C), or three carbon length propyl ester group (compound D). The ester groups strongly affected the molecular properties of the parent ciprofloxacin. As the size of the ester group increased the formula weight, molar volume, and number of rotatable bonds increased. The Log P for these compounds were -0.701, -0.441, -0.065, 0.437 for ciprofloxacin, B, C, and compound D, respectively. Numerical values of dermal permeability coefficient (Kp) increased rapidly as length of the ester carbon chain increased. The immediate consequence of Kp increase is an increased skin penetration rate based on dose and time span of administration. Polar surface area for ciprofloxacin is 74.569 Angstroms2, but decreases to 63.575 Angstroms2 for all three derivatives. All three derivatives of ciprofloxacin showed zero violations of the Rule of 5, indicating these drugs would have favorable bioavailability. Compounds A, B, C, and D were placed into tissue culture with methicillin resistant and susceptible Staphylococcus aureus (MRSA and MSSA, respectively) to determine levels of bacterial growth inhibition. All compounds induced greater than 60 % inhibition of MSSA at concentrations as low as 15.63 micrograms/milliliter. All four compounds induced greater than 80 % inhibition of MRSA at concentratins as low as 15.63 micrograms/milliliter. Development of novel drug designs will benefit the clinical treatment of dangerous infections of MSSA and MRSA.

Liver is affected by secondary iron overload in transfusions dependent β-thalassemia patients. The redox iron can generate reactive oxidants that damage biomolecules, leading to liver fibrosis and cirrhosis. Iron chelators are used to treat thalassemias to achieve negative iron balance and relieve oxidant-induced organ dysfunctions. Green tea (GT) (Camellia sinensis) catechins exhibit anti-oxidation, the inhibition of carcinogenesis, the detoxification of CYP2E1-catalyzed HepG2 cells and iron chelation. The purpose of this study was to investigate the effectiveness of GT in iron-challenged thalassemic mice. Heterozygous BKO type-thalassemia (BKO) mice (C57BL/6) experienced induced iron overload by being fed a ferrocene-supplemented diet (Fe diet) for 8 weeks, and by orally being given GT extract (300 mg/kg) and deferiprone (DFP) (50 mg/kg) for a further 8 weeks. Liver iron content (LIC) was analyzed by TPTZ colorimetric and Perl's staining techniques. Concentrations of liver reduced glutathione (GSH), collagen and malondialdehyde (MDA) were also measured. Dosages of the GT extract and DFP lowered LIC in the Fe diet-fed BKO mice effectively. The extract did not change any concentrations of liver glutathione, collagen and MDA in the BKO mice. Histochemical examination showed leukocyte infiltration in the nearby hepatic portal vein and high iron accumulation in the livers of the iron-loaded BKO mice, however GT treatment lowered the elevated iron deposition. In conclusion, green tea inhibits or delays the deposition of hepatic iron in regularly iron-loaded thalassemic mice effectively. This will prevent the iron-induced generation of free radicals via Haber-Weiss and Fenton reactions, and consequently liver damage and fibrosis. Combined chelation with green tea would be investigated in β-thalassemia patients with iron overload.

A novel series of 2-aryl-1, 2, 4-triazolo [1, 5-a] pyridine derivatives have been synthesized and evaluated for their cytotoxic activities in vitro against Human ovarian cancer cell line (HO-8910) and Human liver cancer cell line (Bel 7402). Most compounds showed high or mediate activity against the cancer cell lines when compared with Cisplatin. Two of them were tested the apoptosis on Bel 7402.

As a follow up of an anti-Flaviviridae project, a new series of variously substituted 2-styryl-benzimidazoles were synthesized and tested in vitro for biological activity. Compounds were tested in cell-based assays against viruses representative of: i) two of the three genera of the Flaviviridae family, i.e. Pestiviruses and Flaviviruses; ii) other RNA virus families, such as Retroviridae, Picornaviridae, Paramyxoviridae, Rhabdoviridae and Reoviridae; iii) two DNA virus families (Herpesviridae and Poxviridae) as well as for cytotoxicity tests, run in parallel with antiviral assays,against MDBK, BHK and Vero 76 cells. In the series examined, new leads emerged against BVDV, CVB-2 and RSV. Compounds 11, 12, 17, 18, 24, 31 exhibited anti-BVDV activity in the concentration range 1.7-16 μM; among them, compound 17 was the most active, with an EC50 = 1.7 μM. Compounds 18 and 21 were equally active against CVB-2, with EC50 values of 7 — 8 μM, while the derivative 30 was active against RSV with EC50= 1 μM and represents a new lead compound.

The powerful inhibitory activity of podophyllotoxin (a natural product) on cell growth led to the development of clinically useful anticancer agents such as etoposide, teniposide, and etopophos. Although, these podophyllotoxin derivatives show good clinical effects against various cancers, its use often results in various undesired side effects, drug resistance, and cytotoxicity towards the normal cells. In order to overcome these limitations, it is essential to search new podophyllotoxin analogues with improved anticancer activity and fewer side effects to gain the maximum benefits for the cancer patients. With this purpose, the cytotoxicity data of two series of podophyllotoxin derivatives against four different cancer cell lines was used to develop 4 QSAR models. Hydrophobic property of the molecules was found one of the most important determining factors for their activity. The developed QSAR models showed a good correlative and predictive abilities having r2 = 0.960 to 0.836 and q2 = 0.911 to 0.705. On the basis of QSAR 1, two compounds (10-10 and 10-11) are suggested as potential synthetic targets. Statistical diagnostics and internal validation (cross validation and Y-randomization) tests have validated all the QSAR models. These QSAR models could be useful in the rational design of potential drug molecules with an enhanced inhibitory potency.

A k nearest neighbor-molecular field analysis (kNN-MFA) of benzimidazole derivatives, a series of hepatitis C virus (HCV) inhibitors, has been performed to determine the factors contributing in the corresponding activities. The energy minimized conformations were obtained by molecular mechanics using VLife QSAR 1.0 package. The developed model was verified by performing leave-one out (LOO) cross-validation, which showed the q2 value of 0.900 and pred_r2 value of 0.783. The model indicates the dominance of the steric field and also points out the regions around the benzamidazole ring where the bulky or less bulky groups can be substituted to increase the activity of the compounds.

The objective of this study was to determine the in vitro transdermal permeation through the human stratum corneum (SC) of the antiretroviral (ARV) drug lamivudine (3TC) (1) and its synthesised methoxypoly(ethylene glycol) (MPEG) carbamates and carbonates in phosphate buffer solution and with the use of Pheroid™ as delivery system, and to establish a relationship, if any, with selected physicochemical properties. The synthesis and in vitro human skin permeation flux of three N4-methoxypoly(ethylene glycol) carbamates (3)-(5) and three 6'-O-methoxypoly(ethylene glycol) carbonates (6)-(8) of lamivudine are reported. The derivatives were synthesised in a two-step process by coupling activated MPEG oligomers of various chain lengths to either the 4-amino or the 6'-hydroxy group of lamivudine. Irrespective of the oligomeric series of derivatives (carbamate or carbonate), the aqueous solubility increased as the MPEG chain lengthened while the solubility in octanol (lipophilicity) remained almost constant. Regardless of the mechanism of diffusion, viz. passive (in PBS) or use of enhancer (Pheroid™), no derivative penetrated the skin better than the parent drug itself. The use of Pheroid™ appeared to retard skin permeation.

Polyketides are secondary metabolites of microorganisms synthesized by serialized reactions of a set of enzymes called polyketide synthases (PKS). As many infectious microorganisms are acquiring tolerance to antibiotics, the need for novel medicines is increasing. Recently, various methods are being used for drug discovery, including gene manipulation for biosynthesis of antibiotics such as polyketides. Due to their importance as drugs, the volume of data on polyketides is rapidly increasing. In the present paper, by using SEARCHPKS and ASMPKS servers, domain identification, and domain organization, substrate specificity of AT domain, domain assembly and chemical moiety of three Actinomycetes i.e., Mycobacterium abscessus, Micromonospora chalcea and Streptomyces achromogenes are analyzed. So far, no secondary metabolite of any of these bacteria is known. Here, it was demonstrated that KR1, KR2 and KR3 domains from M. chalcea, KR5 domain from M. abscessus and KR6 domain from S. achromogenes could be assigned as B1-type, while KR4 domain from M. abscessus and KR7 domain from S. achromogenes could be assigned as A1 type. Substrate specificity of AT1 and AT2 of M. abscessus predicted to be malonate. AT2 domain of PKS protein from S. achromogenes also selected as malonate. Methylmalonate substrate was predicted for AT1 and AT3 domains. All of the AT domains in modules of PKS protein of M. chalcea were predicted to be specific for methylmalonate. Analysis of folding rate of these proteins showed that the logarithm of (kf) decreased in proportion to protein chain length. We have also performed a comprehensive phylogenetics analysis of AT and DH domains with FabA, FabZ and dehydratase proteins of various bacteria and secondary metabolites. The phylogenetic tree derived from these sequences reflects the long joint evolution process.

The purpose of this study was to synthesize and determine the in vitro transdermal penetration of cytarabine and its 5'-alkyl esters and to establish a correlation, if any, with selected physicochemical properties. The n-alkyl esters were synthesized by acylation of cytarabine (1) at its pharmacophoric 5'-OH. The transdermal flux values of (1) and its esters were determined in vitro using Franz diffusion cell methodology. Aqueous solubility and log D (pH 7.4) values were determined and assessed for correlation to transdermal flux. An inverse relation was observed between the water solubility (Sw) and log D values. Of all esters, (4) exhibited the highest flux value of 22.2 nmol.cm-2.h-1, which is significantly different to that of the parent drug cytarabine (3.70 nmol.cm-2.h-1). No trend was found between water solubility and flux values.