Medicinal Chemistry - Volume 3, Issue 6, 2007

Bioisosterism represents one approach used by the medicinal chemist for the rational modification of lead compounds into safer and more clinically effective agents. Bioisosteres are substituents or groups that have chemical or physical similarities and that produce broadly similar biological effects. The sulfone moiety is recognized as a nonclassical bioisostere for replacement of the carbonyl group. When sulfonyl derivatives 5a-e were compared with carbonyl compounds 4a-e, the sulfone substitution dramatically decreased the antiproliferative activity of the series.

A series of thioamides were designed as bio-isosteres to the non-nucleoside reverse transcriptase inhibitor trovirdine by replacement of the thiourea NH groups with methylene groups. Eight thioamides were synthesized and in vitro tested for inhibitory effects on the activity of HIV-1 reverse transcriptase wild and mutant types. Three of the 8- thioamides exhibited enzyme inhibitory activities with IC50 values below 100 μM. While compound (2) exhibited activity against the mutant strain L100I with IC50 of 70.1 μM, compound (4) showed activity against the mutant strain K103N with IC50 of 92.7 μM, and compound (8) with activity against the wild type enzyme with IC50 of 8.9 μM. Each of the three thioamides could serve as a lead compound for further activity optimization.

A series N,N'-bis[4-(1H(2H)-benzotriazol-1(2)-yl)phenyl]alkyldicarboxamides (3a-f and 5a-j) were prepared starting from their already known (1a-d) and (4a-c) or new (4d) amine parents. Because of the antiviral activity of several N-[4-(1H(2H)-benzotriazol-1(2)-yl)phenyl]alkylcarboxamides previously reported, title compounds were evaluated in vitro for cytotoxicity and antiviral activity against viruses representative of Picornaviridae, [i.e. Enterovirus Coxsackie B2 (CVB-2) and Polio (Sb-1)] and of two of the three genera of the Flaviviridae [Bovine Viral Diarrhea Virus (BVDV) and Yellow Fever Virus (YFV)]. Furthermore, because of the in silico activity against the RNA-dependent RNA-helicase of Polio 1 previously reported, title compounds were evaluated against the 3D model of the Sb-1 helicase and against the 2D model of the CVB-2 helicase. As a reference we used the antiviral and in silico activities of an imidazo counterpart of the title compounds, N,N'-bis[4-(2-benzimidazolyl)phenyl]alkyldicarboxamides (III) that other authors reported to be able to inhibit the corresponding enzyme of Hepatitis C Virus (HCV). In cell-based antiviral assays, N,N'-bis[4-(1H-benzotriazol- 1-yl)phenyl]alkyldicarboxamides (3a-f) resulted completely inactive whereas the bis-5,6-dimethyl-benzotriazol-2-yl derivatives (5d-f) exhibited good activity against the Enteroviruses, (EC50s ranged between 7 and 11 μM against CVB-2 and 19-52 against Sb-1). Interestingly, bis-5,6-dichloro-benzotriazol-2-yl derivatives (5h-j) showed very selective activity against CVB-2 (EC50s = 4-11 μM) whereas they resulted completely inactive against all the other viruses screened. In general, all title compounds showed a good cytotoxicity profile in MT-4 cells. Molecular modeling investigations showed that active compounds may interact with the binding site of the Sb-1 helicase and that their free binding energy values are in agreement with their EC50s values.

The design, synthesis and anti HIV-1 replication inhibition of 3-(cyclopropylethynyl)-3-hydroxy-indolin-2- ones, analogues of efavirenz (Sustiva™), are described. Different substituted isatins were used to generate final products that contain pharmacophoric features for RT inhibition, such as the oxoindole and cyclopropylethynyl groups. The suitability of the indolin-2-one ring in the planned compounds in replacement to the benzoxazinone ring of efavirenz was proven, since compound 15 presented a greater activity than efavirenz against HIV-1 replication and was not significantly cytotoxic.

Oxybutynin (1) is a non-selective muscarinic receptor antagonist that is used clinically for the treatment of urinary incontinence. The major metabolite of oxybutynin in humans is desethyloxybutynin (2). We have prepared the enantiomers of 1 and 2 and evaluated their ability to displace N-CT3-scopolamine chloride (3H-NMS) binding on human cloned muscarinic m1-5 receptors. Compounds 1 and 2 potently displaced 3H-NMS binding at m1, m3 and m4 receptors, but were less potent at the m2 and m5 subtypes. However, metabolite 2 was more potent than the parent compound 1 in the binding assay. In general the R enantiomers were more potent than their respective S enantiomers. Therefore, we suggest that the cholinergic side effects associated with 2 may be due to its greater apparent potency with m1 and m3 receptors, especially of its R-enantiomer, when compared with parent drug 1.

20α-hydroxysteroid dehydrogenase (AKR1C1) plays a key role in the metabolism of progesterone and other steroid hormones, thereby regulating their action at the pre-receptor level. AKR1C1 is implicated in neurological and psychiatric conditions such as catamenial epilepsy and depressive disorders. Increased activity of AKR1C1 is associated with termination of pregnancy and the development of breast cancer, endometriosis and endometrial cancer. Inhibition of the undesired activity of AKR1C1 will help reduce risks of premature birth, neurological disorders and the development of cancer. In order to identify potential leads for new inhibitors of AKR1C1 we adopted a virtual screening-based approach using the automated DOCK program. Approximately 250,000 compounds from the NCI database were screened for potential ligands based on their chemical complementarity and steric fit within the active site of AKR1C1. Kinetic analysis revealed 3,5-diiodosalicylic acid, an analogue of salicylic acid, as a potent competitive inhibitor with respect to the substrate 5β-pregnane-3α,20α-diol with a Ki of 9 nM. Aspirin, which is a well known salicylic acid-based drug, was also found to inhibit AKR1C1 activity. This is the first report to show aspirin (IC50=21 μM) and its metabolite salicylic acid (IC50=7.8 μM) as inhibitors of AKR1C1.

In the present study we describe the synthesis of a new series of 1,2,4-triazoles: [3-(arylmethyl)thio-5-aryl-4H- [1,2,4]triazol-4-yl]acetic acids 5a-g, [5-(arylmethyl)thio-3-aryl-1H-[1,2,4]triazol-1-yl]acetic acids 8a-d, and [3-(arylmethyl) thio-5-aryl-1H-[1,2,4]triazol-1-yl] acetic acids 9a-d. These compounds were tested in binding assays to evaluate their ability as ligands for human ETA and ETB receptors stably expressed in CHO cells; some of the tested compounds showed affinity in the micromolar range.

The synthesis of a series of new N-OMe fluoro-indoles with melatoninergic activity in the Xenopus melanophore assay is described. All of the 4-F substituted compounds, 22a-e and 25a,b, were antagonists on the clonal Xenopus melanophore line. Conversely, the 5-F substituted analogs (15a-e) did not share the same pharmacological profile, as two of them, compounds 15d (R=c-C3H5) and 15e (R=c-C4H7), exhibited a weak agonistic and partial agonistic activity, respectively, whilst the other three (15a-c) were all agonists. It seems that in this case the nature of the response (agonist or antagonist activity) is solely dependent on the shape of the R group.

Antedrug approach of the corticosteroids has been described as a fundamentally sound approach for the development of safer anti-inflammatory steroids devoid of systemic side effects. In our continued efforts under the antedrug paradigm, we have recently extended this effort to synthesize the 21-thioalkylether derivatives of methyl 16- prednisolonecarboxylates. The 21-mesylate of the methyl-16-perdnisolonecarboxylates and 9-fluoro-17-dehydro methyl 16-prednisolonecarboxylate were reacted with Na-thioalkoxides to furnish the desired thioalkylethers in 60-75% yields. These newly synthesized thioalkylether steroid series were tested for their in vitro metabolism and corticosteroid receptor binding affinity. They were metabolized in predictable manner to inactive 16-carboxylic acids. All the newly synthesized antedrugs showed lowered glucocorticoid receptor binding affinity than prednisolone indicating that the replacement of the 21-OH function with thioalkylether of the 16-prednisolone carboxylate esters decreases their receptor binding affinity.

A three dimensional Quantitative Structure Activity Relationship (3D-QSAR) model for a series of (S)-3-Aryl- 5-substituted oxazolidinones was developed to gain insights into the design for potential new antibacterial agents. It was found that the Comparative Molecular Field Analysis (CoMFA) method yielded good results while the Comparative Molecular Similarity Indices Analysis (CoMSIA) was less satisfactory. The CoMFA method yielded a cross-validated correlation coefficient q2 = 0.681, non-cross-validated R2 = 0.991, SE (Standard Error ) = 0.054, and the value of statistical significance measure F = 266.98. The relative steric and electrostatic contributions are 0.542 and 0.458, respectively. These results indicate that the model possesses a high predictivity. Guided by this model, three new compounds were synthesized. All these compounds exhibit inhibitory activity; two of them were shown having high activity (MIC = 1.0μg/ml). The activity observed by experiments was in good agreement with the theoretical one. It is anticipated that the present model would be of value in facilitating design of new potent antibacterial agents.

Opioidmimetics containing 3-[H-Dmt-NH-(CH2)m]-6-[H-Dmt-NH-(CH2)n]-2(1H)-pyrazinone symmetric (m = n, 1-4) (1 - 4) and asymmetric (m, n = 1 - 4) aliphatic chains (5 - 16) were synthesized using dipeptidyl chloromethylketone intermediates. They had high μ-affinity (Kiμ = 0.021 - 2.94 nM), δ-affinity (Kiδ = 1.06 - 152.6 nM), and μ selectivity (Kiδ/Kiμ = 14 - 3,126). The opioidmimetics (1 - 16) exhibited μ agonism in proportion to their μ-receptor affinity. δ- Agonism was essentially lacking in the compounds except (4) and (16), and (1) and (2) indicated weak δ antagonism (pA2 = 6.47 and 6.56, respectively). The data verify that a specific length of aliphatic linker is required between the Dmt pharmacophore and the pyrazinone ring to produce unique μ-opioid receptor ligands.

In this work we examined the affinity and the selectivity of V. adscendens, Iresine herbstii Hook. (Amaranthaceae) and Brugmansia arborea (L.) Lagerheim (Solanaceae) towards 5-HT1A, 5-HT2A, 5-HT2C serotononergic, D1 and D2 dopaminergic, α1 and α2 adrenergic receptors by radioligand assays. The results show weak affinity to 5-HT1A only for the aqueous extract of V. adscendens and no affinity for 5-HT2A, 5- HT2C serotononergic receptors, α1 and α2 adrenergic receptors and D2 receptors. As it regards D1 receptors, only for the methanolic extract the IC50 value was determinable. The data obtained for I. herbstii extracts have shown a low affinity for the 5-HT1A receptor (22.44%) and no affinity for 5- HT2A receptor. Otherwise these extracts showed affinity for 5-HT2C receptor but only for the methanolic extract the IC50 value (inhibitory concentration 50%) was: 34.8 μg/ml. The B. arborea aqueous extract displayed weak affinity for all receptors tested, the highest levels of inhibition at the maximum concentration tested (125 μg/ml) were 38% for the 5-HT1A , 16% for the 5-HT2A and 39% for the 5-HT2C receptor.The results of our experiments indicate that V. adscendens, Iresine herbstii and Brugmansia arborea were able to interact with the central 5-HT receptors thus confirming their ritual use.

Emerging concepts in the construction of nanostructures hold immense potential in the areas of drug delivery and targeting. Such nanoscopic assemblies/structures, similar to natural proteins and self-associating systems, may lead to the formation of programmable soft structures with expanded drug delivery options and the capability to circumvent firstpass metabolism. This article aims to illustrate key recent developments and innovative bioinspired design paradigms pertaining to peptide-containing self-assembled tubular and vesicular soft structures. Soft structures are composed of components that self-assemble to reveal diverse morphologies stabilized by weak, noncovalent interactions. Morphological properties of such structures and their ability to encapsulate drugs, biologicals and bioactive small molecules, with the promise of targeted delivery, are discussed.