Medicinal Chemistry - Volume 3, Issue 2, 2007

The antileishmanial and antimalarial activity of methoxy-substituted chalcones (1,3-diphenyl-2-propen-1-ones) is well established. The few analogs prepared to date where the 3-phenyl group is replaced by either a pyridine or naphthalene suggest these modifications are potency enhancing. To explore this hypothesis, sixteen 3-naphthalenyl-1-phenyl- 2-prop-1-enones and ten 1-phenyl-3-pyridinyl-2-prop-1-enones were synthesized and their in vitro efficacies against Leishmania donovani and Plasmodium falciparum determined. One inhibitor with submicromolar efficacy against L. donovani was identified (IC50 = 0.95 μM), along with three other potent compounds (IC50 < 5 μM), all of which were 3- pyridin-2-yl derivatives. No inhibitors with submicromolar efficacy against P. falciparum were identified, though several potent compounds were found (IC50 < 5 μM). The cytotoxicity of the five most active L. donovani inhibitors was assessed. At best the IC50 against a primary kidney cell line was around two-fold higher than against L. donovani. Being more active than pentamidine, the 1-phenyl-3-pyridin-2-yl-2-propen-1-ones have potential for further development against leishmaniasis; however it will be essential in such a program to address not only efficacy but also their potential for toxicity.

The chloroform and hexane fractions and their sub-fractions of Polygonum bistorta (Polygonaceae) were evaluated for their cytotoxic activity against P338 (Murine lymphocytic leukaemia), HepG2 (Hepatocellular carcinoma), J82 (Bladder transitional carcinoma), HL60 (Human leukaemia), MCF7 (Human breast cancer) and LL2 (Lewis lung carcinoma) cancer cell lines in culture. Both the chloroform and hexane fractions and a few of their sub-fractions showed moderate to very good activity against P388, HL60 and LL2 cancer cell lines. Both active and non-active fractions were further investigated for their chemical constituents. A total of nine compounds, viz. 24(E)-ethylidenecycloartanone (1), 24(E)-ethylidenecycloartan-3 α-ol (2), cycloartane-3,24-dione (3), 24-methylenecycloartanone (4), friedelin (5), 3 -β friedelinol (6), β -sitosterol (7), γ-sitosterol (8) and β-sitosterone (9) were isolated. One of the pure compounds, 24(E)- ethylidenecycloartanone 1, which was obtained in sufficient quantity, was tested for its cytotoxicity against P388, LL2, HL60 and WEHI164 (Murine fibrosarcoma) cancer cell lines but was found to have no activity even at a concentration of 100 μg/mL.

New series of 5-alkoxy-benzopyranopyrimidine derivatives were developed from the chemical modulation of the substituent in position 2 of the scaffold, with the aim to produce analgesic/antiphlogistic agents more potent than analogues previously reported. The 2-hydrazino derivatives exhibited a good analgesic activity in writhing test; the analgesic doses of the compounds did not affect mice spontaneous locomotor activity thus any confounding sedative effect could be excluded. These derivatives revealed an aspirin-like profile with a strong inhibition of AA-induced platelet aggregation, probably due to a strong, non selective, inhibition of cyclooxygenases. In spite of the inhibition of COX activity displayed in vitro, the compounds did not cause gastric damage in rats after acute oral administration. A different pharmacological profile was observed for the 2-azido derivatives, particularly in vivo.

Selective estrogen receptor modulators (SERMs) such as tamoxifen and toremifene are clinically useful drugs in the endocrine treatment of estrogen receptor positive breast cancer while raloxifene is an effective intervention for osteoporosis. In an ongoing SERM discovery programme we now report the synthesis of a series of 3-benzyl-4,6-diarylhex- 3-enes and 3,4,6-triarylhex-3-enes containing an extended flexible core structure. In these novel structures, the ethylene group acts as a flexible spacing group linking the aryl Ring A or Ring B with the core alkene group. In the benzyl-4,6- diarylhex-3-ene series an additional methylene group is inserted as a spacing group between the aryl ring C and the ethylene core group. These products demonstrated antiproliferative activity against the MCF-7 human breast cancer cell line. The alkene compounds were also shown to have binding affinity for the estrogen receptor alpha (IC50 values for the most active compounds in the range 0.110-0.293?M) together with selectivity for ER / . The compounds demonstrated antiestrogenic activity in Ishikawa cells with low estrogenic stimulation. The structure-activity relationships for the active ligands were further explored in a computational study where docked structures of the active compounds were compared with the X-ray crystal structures for the complexes of ER with 4-hydroxytamoxifen and ER with raloxifene. The alignment of the aromatic rings B and C of the compounds within the ligand binding domain could then be correlated with their observed ER / selectivity.

The dinuclear platinum complex bis(acetato)diammine-bis-μ-acetato diplatinum (II) dihydrate has been previously shown to exert profound cytotoxicity in diverse tumor cell lines, while being far less detrimental than the clinically applied platinum drugs against some susceptible to platinum toxicity non-malignant cellular populations. In the present study we report the investigation of the cellular accumulation kinetics and apoptosis induction of the dinuclear complex in K-562, its potent in vivo antineoplastic activity against L1210 leukemia and Lewis lung carcinoma tumor models and its lower nephrotoxicity, myelosuppresive potential and clastogenicity in vivo relative to cisplatin.

A quantitative structure-activity relationship study has been made on some pyranyl hydroxamic acid analogs acting as matrix metalloproteinase (MMP) inhibitors. The inhibition potencies of two different series of compounds against two MMP enzymes (MMP-1 and MMP-13) have been analyzed and found to be well correlated with hydrophobic and some indicator parameters of the substituents. In both the cases, hydrophobic parameter of substituents has been found to be a dominant factor. The results of this study led to discuss the selectivity of the compounds for MMP-13 over MMP-1.

Lipoxygenases (LO) have been implicated in several inflammatory diseases such as asthma, immune disorders, and cancers. Lipoxygenases play an essential role in the biosynthesis of the leukotrienes. Leukotrienes have been implicated as mediators in the pathophysiology of inflammatory diseases, host defense reactions and they were found to play important role in the propagation of the diseases states, exacerbating the local events and ultimately leading to tissue damage. As a consequence of these broad biological implications, there is a great interest in synthesising new compounds with this activity. The synthesis of new amides of aryl acetic acid is described. The structures of the synthesized compounds were confirmed by spectral and elemental analysis. Since lipophilicity is a significant physicochemical property determining distribution, bioavailability, metabolic activity and elimination, their lipophilicity is experimentally determined from RPTLC method. Several parameters were theoretically calculated and were used for a QSAR study. The compounds are tested in vitro on: a) soybean lipoxygenase inhibition, b) interaction with 1,1-diphenyl-2-picryl-hydrazyl (DPPH) stable free radical, c) the HO mediated oxidation of DMSO, d) inhibition of lipid peroxidation, e) scavenging of superoxide anion radicals f) interaction with glutathione and g) in vivo for the inhibition of carrageenin induced rat paw edema. The compounds present significant antioxidant activities, medium anti-inflammatory activity and potent inhibition of soybean lipoxygenase as a result of their physicochemical features.

Pharmacophore mapping is one of the major elements of drug design in the absence of structural data of the target receptor. The tool initially applied to discovery of lead molecules now extends to lead optimization. Pharmacophores can be used as queries for retrieving potential leads from structural databases (lead discovery), for designing molecules with specific desired attributes (lead optimization), and for assessing similarity and diversity of molecules using pharmacophore fingerprints. It can also be used to align molecules based on the 3D arrangement of chemical features or to develop predictive 3D QSAR models. This review begins with a brief historical overview of the pharmacophore evolution followed by a coverage of the developments in methodologies for pharmacophore identification over the period from inception of the pharmacophore concept to recent developments of the more sophisticated tools such as Catalyst, GASP, and DISCO. In addition, we present some very recent successes of the widely used pharmacophore generation methods in drug discovery.

This article reviews the current status of classes of HIV-1 integrase enzyme inhibitors. These classes include peptide-based inhibitors, natural products, polyhydroxylated aromatics, diketo acids, naphthyridines, and sulfonated compounds including sulfonic acids. Discussions of structure activity relationships are presented and include the current overview of the structure-based model, suitable for the further design and development. To date, the advances in the medicinal chemistry of HIV-1 integrase inhibitors have relied mostly on ligand-based designs leading to most displaying similar binding interactions within the active site or at the dimer interface. This paves the way for single enzyme mutations rendering entire compound classes inactive and thus, the requirement for second and third generation inhibitors with novel modes of binding is apparent. To facilitate future structure-based drug design efforts, a model of the biologically relevant structure of the HIV-1 integrase enzyme, a dimer of dimers has also been discussed.