Optimization of the Pharmacophore Model for 5-HT₇R Antagonism. Design and Synthesis of New Naphtholactam and Naphthosultam Derivatives

Abstract

We present in this study an optimization of a preliminary pharmacophore model for 5-HT(7)R antagonism, with the incorporation of recently reported ligands and using an efficient procedure with the CATALYST program. The model consists of five features: a positive ionizable atom (PI), a H-bonding acceptor group (HBA), and three hydrophobic regions (HYD). This model has been supported by the design, synthesis, and biological evaluation of new naphtholactam and naphthosultam derivatives of general structure I (39-72). A systematic structure-affinity relationship (SAFIR) study on these analogues has allowed us to confirm that the model incorporates the essential structural features for 5-HT(7)R antagonism. In addition, computational simulation of the complex between compound 56 and a rhodopsin-based 3D model of the 5-HT(7)R transmembrane domain has permitted us to define the molecular details of the ligand-receptor interaction and gives additional support to the proposed pharmacophore model for 5-HT(7)R antagonism: (i) the HBA feature of the pharmacophore model binds Ser(5.42) and Thr(5.43), (ii) the HYD1 feature interacts with Phe(6.52), (iii) the PI feature forms an ionic interaction with Asp(3.32), and (iv) the HYD3 (AR) feature interacts with a set of aromatic residues (Phe(3.28), Tyr(7.43)). These results provide the tools for the design and synthesis of new ligands with predetermined affinities and pharmacological properties.

Exploring Acyclic Nucleoside Analogues as Inhibitors of Mycobacterium tuberculosis Thymidylate Kinase

“…]indol-2(1H)-one at the lactam nitrogen [27] under identical conditions to those already described in our first series of compounds is well described, allowing us to reach the targeted analogues in a two-step sequence. Moreover, the 6-position of benzoA C H T U N G T R E N N U N G [c,d]indol-2(1H)-one can be easily nitrated permitting the study of how substituents at this position affect the interaction with the enzyme.…”

“…However, as this amino compound was quite unstable in our hands, the amino derivative obtained after hydrogenation was directly transformed into its acetamide derivative (30) and was used as such in the next steps. Thus, reaction of benzoA (28) or its 6-nitro analogue (29) [28] with (Z)-1,4-dichloro-2-butene in the presence of NaH, as described for other halides, [27,29] afford-ed the monosubstituted compounds 31 and 32 in 84 and 54 % yields, respectively. Alternatively, the 6-acetamide derivative 30 reacted with (Z)-1,4-dichloro-2-butene in the presence of NaOMe afforded 33 in 67 % yield.…”

“…Further treatment of 36 with HCl in dioxane at reflux afforded the 6-amino derivative 37 in 98 % yield. As a naphthosultam ring can be considered a good isosteric replacement for a naphtholactam, [27] the synthesis of the naphthosultam derivative 40 was undertaken following an analogous synthetic approach. Reaction of 38 with (Z)-1,4-dichloro-2-butene in the presence of NaH afforded the chloro intermediate 39 that reacted with silylated thymine (Scheme 6).…”

“…Concerning the modifications at the distal substituent, the initial set of compounds (25)(26)(27) kept the inhibitory potency against the dTMP phosphorylation catalyzed by TMPKmt, as shown in Table 1. In particular, compound 27 (K i = 1.4 mm) was equipotent to the parent naphthalimide derivative 17, indicating that at least one of the carbonyl groups of the naphthalimide substituent was not required for interaction with the target enzyme.…”

“…The reaction was finally neutralized by addition of NaOH 50 %. Volatiles were removed and the residue was purified by flash column chromatography (EtOAc/Et (27). NaBH 4 (378 mg, 10.0 mmol) was added in portions to a solution of 25 (377 mg, 1.0 mmol) in trifluoroacetic acid (TFA) (2 mL) at 0 8C.…”