HIV protease inhibitors with picomolar potency against PI-Resistant HIV-1 by extension of the P3 substituent

A biaryl pyridylfuran P(3) substituent on the hydroxyethylene isostere scaffold affords HIV protease inhibitors (PI's) with picomolar (IC(50)) potency against the protease enzymes from PI-resistant HIV-1 strains. Inclusion of a gem-dimethyl substituent afforded compound 3 with 100% oral bioavailability (dogs) and more than double the t(1/2) of indinavir. Inhibition of multiple P450 isoforms is dependent on the regiochemistry of the pyridyl nitrogen in these compounds.     

Thalassiolins A-C: new marine-derived inhibitors of HIV cDNA integrase

Human immunodeficiency virus (HIV) replication requires integration of viral cDNA into the host genome, a process mediated by the viral enzyme integrase. We describe a new series of HIV integrase inhibitors, thalassiolins A-C (1-3), isolated from the Caribbean sea grass Thalassia testudinum. The thalassiolins are distinguished from other flavones previously studied by the substitution of a sulfated beta-D-glucose at the 7-position, a substituent that imparts increased potency against integrase in biochemical assays. The most active of these molecules, thalassiolin A (1), displays in vitro inhibition of the integrase catalyzed strand transfer reaction (IC50=0.4 microM) and an antiviral IC50 of 30 microM. Molecular modeling studies indicate a favorable binding mode is probable at the catalytic core domain of HIV-1 integrase.     

Anti-HIV properties of cationic fullerene derivatives

A series of regioisomeric bis-fulleropyrrolidines bearing two ammonium groups have been synthesized and their activities against HIV-1 and HIV-2 have been evaluated. Two trans isomers have been endowed with interesting antiviral properties, confirming the importance of the relative positions of the substituent on the C(60) cage. In addition, reduced amphiphilicity of molecules to other compounds previously reported decreases their cytotoxicity in CEM cell cultures. None of the compounds showed any inhibitory activity against a variety of DNA and RNA viruses other than HIV.     

Design,Synthesis, and Anti‐HIV‐1 Evaluation of a Novel Series of 1,2,3,4‐Tetrahydropyrimidine‐5‐Carboxylic Acid Derivatives

A series of tetrahydropyrimidine derivatives ( 2a – 2l ) were designed, synthesized, and screened for anti‐HIV‐1 properties based on the structures of HIV‐1 gp41 binding site inhibitors, NB ‐2 and NB ‐64 . A computational study was performed to predict the pharmacodynamics, pharmacokinetics, and drug‐likeness features of the studied molecules. Docking studies revealed that the carboxylic acid group in the molecules forms salt bridges with either Lys574 or Arg579. Physiochemical properties (e.g., molecular weight, number of hydrogen bond donors, number of hydrogen bond acceptors, and number of rotatable bonds) of the synthesized compounds confirmed and exhibited that these compounds were within the range set by Lipinski's rule of five. Compounds 2e and 2k with 4‐chlorophenyl substituent and 4‐methylphenyl group at C(4) position of the tetrahydropyrimidine ring was the most potent one among the tested compounds. This suggests that these compounds may serve as leads for development of novel small‐molecule HIV‐1 inhibitors.     

Design,Efficient Synthesis,and Anti‐HIV Activity of 4′‐C‐Cyano‐ and 4′‐C‐Ethynyl‐2′‐deoxy Purine Nucleosides

Some 4′‐C‐ethynyl‐2′‐deoxy purine nucleosides showed the most potent anti‐HIV activity among the series of 4′‐C‐substituted 2′‐deoxynucleosides whose 4′‐C‐substituents were methyl, ethyl, ethynyl and so on. Our hypothesis is that the smaller the substituent at the C‐4′ position they have, the more acceptable biological activity they show. Thus, 4′‐C‐cyano‐2′‐deoxy purine nucleosides, whose substituent is smaller than the ethynyl group, will have more potent antiviral activity. To prove our hypothesis, we planned to develop an efficient synthesis of 4′‐C‐cyano‐2′‐deoxy purine nucleosides (4′‐CNdNs) and 4′‐C‐ethynyl‐2′‐deoxy purine nucleosides (4′‐EdNs). Consequently, we succeeded in developing an efficient synthesis of six 2′‐deoxy purine nucleosides bearing either a cyano or an ethynyl group at the C‐4′ position of the sugar moiety from 2′‐deoxyadenosine and 2,6‐diaminopurine 2′‐deoxyriboside. Unfortunately, 4′‐C‐cyano derivatives showed lower activity against HIV‐1, and two 4′‐C‐ethynyl derivatives suggested high toxicity in vivo.     

Structural requirements for potent human spermicidal activity of dual-function aryl phosphate derivative of bromo-methoxy zidovudine (compound WHI-07)

WHI-07, a novel bromo-methoxy-substituted aryl phosphate derivative of zidovudine (ZDV), is a potent dual-function contraceptive agent. Although the bromo-methoxy functional groups in the thymine ring of its ZDV are very important for its sperm-immobilizing activity (SIA), the importance of the esterification of the phosphate group with an amino acid side chain and the identity of the para substituent in the aryl moiety remain unclear. In the present study, we have synthesized 23 new analogues of WHI-07 by replacing the alanine (Ala) side chain with different amino acids containing nonpolar side chains, namely tryptophan (Trp), proline (Pro), phenylalanine (Phe), leucine (Leu), methionine (Met), valine (Val), or glycine (Gly). The para substituents on the aryl moiety included bromo, chloro, fluoro, nitro, or methoxy groups. The SIA of each of the 23 WHI-07 analogues was evaluated by computer-assisted sperm analysis. The potential cytotoxicity of these compounds against normal human ectocervical and endocervical epithelial cells was evaluated using MTT (3-[4, 5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) cell viability assays. The replacement of the Ala side chain of WHI-07 with Val, Leu, or Phe led to a complete loss of SIA (EC(50) values > 500 microM), whereas replacement with Trp reduced the SIA by 4-fold. The presence of para substituents on the phenyl moiety led to significant alterations in SIA. The anti-human immunodeficiency virus (HIV) activity of Trp-containing WHI-07 analogues was also diminished. Our finding highlights the necessity of Ala side chain and the presence of electron-withdrawing para-bromo substituent on the phenyl moiety in addition to bromo-methoxy functionalization groups on the thymine ring in order for the phosphoramidate derivatives of ZDV to be effective dual-function spermicidal agents. Unlike the detergent-type microbicide, nonoxynol-9, which was cytotoxic to normal human ectocervical and endocervical epithelial cells (IC(50) values of 22 microM and 16 microM, respectively) at spermicidal concentrations (EC(50) = 81 microM), WHI-07 and its active analogues were selectively spermicidal without cytotoxicity against female genital tract epithelial cells. WHI-07 and its Trp analogues hold particular clinical promise for the development of novel, nondetergent-type prophylactic contraceptives for the prevention of heterosexual HIV/acquired immunodeficiency syndrome transmission.     

Quantitative structure-activity relationship study on affinity profile of a series of 1,8-naphthyridine antagonists toward bovine adenosine receptors

The affinity profiles for the bovine adenosine receptors, A(1) and A(2A), of a series of 1,8-naphthyridine derivatives were quantitatively analyzed using physicochemical and structural parameters of the substituents, present at varying positions of the molecules. The derived significant correlation, for bovine A(1) receptor, suggested that a R(1) substituent having a higher van der Waals volume, a R(2) substituent being a hydrogen-bond donor and a R(3) substituent able to transmit a higher field effect are helpful in augmenting the pK(i) of a compound. Similarly the study, pertaining to bovine A(2A) receptor, revealed that a less bulky substituent at R(2) and a strong electron-withdrawing substituent at R(3) are desirable in improving the binding affinity of a compound while substituents at R(1) remain insignificant to any interaction.     

Hydrophobicity in the design of P2/P2' tetrahydropyrimidinone HIV protease inhibitors

As part of an ongoing effort in understanding the role of hydrophobicity in the design of nonpeptidic HIV protease inhibitors, the QSAR study on P2/P2' tetrahydropyrimidinone is presented in this report. Our results suggest that the balance of hydrophobicity and a volume- dependent polarizability term plays a key role in the inhibition of the viral protease by these inhibitors. The size of the substituent of ligands at particular positions that induce steric fit is crucial. The role of hydrophobicity in the design of tetrahydropyrimidinone is discussed. It has been found that a sufficient spread in the data is required to observe the optimum value of ClogP for these inhibitors.     

Quantitative structure-activity relationship study of new potent and selective antagonists at the 5-HT(1A) and adrenergic alpha(1d) receptors: Derivatives of spiroethyl phenyl(substituted)piperazine

The antagonistic activities of derivatives of spiroethyl phenyl(substituted)piperazine at the 5-HT(1A) and adrenergic alpha(1d) receptors is quantitatively analyzed employing physicochemical and structural parameters. The derived correlation equation revealed that a substituent, other than 2-CH3 in the phenyl ring, having higher molar refraction, MR, and a substituent producing higher positive field effect at the 3-position are beneficial in increasing the binding affinity at the 5-HT(1A) receptor. In addition, a less hydrophobic substituent at the 4-position is also helpful in augmenting the binding affinity. The 5-R substituents which have higher MR values, however, elicit a detrimental effect. Two disubstituted compounds which are not present in the original data-set and have higher theoretical binding affinities are designed from the correlation equation. These compounds consisting of 2-OCH(CH3)2, 3-Cl and 2-C3H7, 3-Cl in the phenyl ring, have theoretical pK(i) values 10.57 and 10.12 respectively. For the adrenergic alpha(1d) receptor, a less bulky group at the 3-position with 5-Cl (or simply a 3-Cl) is advantageous in increasing the binding affinity. Likewise, a substituent exhibiting a less negative resonance effect at the 4-position and the substituent with low polarizability and showing more a negative resonance effect at the 5-position are suitable for enhancement of the binding affinity. The analysis provides the grounds for rationalizing substituent selection in designing better potency antagonists in the series.     

A novel and facile preparation of bremazocine enantiomers through optically pure N-norbremazocines

In order to provide ready access to multigram quantities of the optically pure bremazocines [(-)- and (+)-9,9-dimethyl-5-ethyl-2-hydroxy-2-(1-hydroxy-cyclopropylmethyl)-6,7-benzomorphan)], we have developed an improved non-chromatographic synthesis, and determined the optical purity of their N-nor precursors using a rapid and relatively simple 1H NMR method based on diastereomeric derivatization with optically pure 1-phenylethylisocyanate. This method of determining optical purity should be readily amenable to similar systems containing phenolic amino functionalities. Finally, a greatly simplified methodology for introduction of the N-(1-hydroxycyclopropylmethyl) substituent in bremazocine is described. The improved synthetic method-the overall yield was increased about 3-fold-combined with the practical methodology to determine optical purity will considerably facilitate the employment of these enantiomers as pharmacological tools for examination of the kappa-opioid receptor system, as well as their evaluation as drug abuse treatment agents. This synthesis will also enable the study of these enantiomers for other, non-classical applications (e.g., treatment agents for HIV).     

Parallel synthesis and nucleic acid binding properties of C(6')-α-functionalized bicyclo-DNA

Two novel bicyclo-T nucleosides carrying a hydroxyl or a carboxymethyl substituent in C(6')-α-position were prepared and incorporated into oligodeoxynucleotides. During oligonucleotide deprotection the carboxymethyl substituent was converted into different amide substituents in a parallel way. T(m)-measurements showed no dramatic differences in both, thermal affinity and mismatch discrimination, compared to unmodified oligonucleotides. The post-synthetic modification of the carboxymethyl substituent allows in principle for a parallel preparation of a library of oligonucleotides carrying diverse substituents at C(6'). In addition, functional groups can be placed into unique positions in a DNA double helix.