Synthesis of 6-arylvinyl analogues of the HIV drugs SJ-3366 and Emivirine

This paper reports the synthesis and the antiviral activities of a series of 6-arylvinyl substituted analogues of SJ-3366, a highly potent agent against HIV. The objective was to investigate whether substitution of the 6-arylketone with a 6-arylvinyl group could lead to an improved antiviral activity against HIV-1. The most active compounds 1-ethoxymethyl, 1-(2-propynyloxymethyl), and 1-(2-methyl-3-phenylallyloxymethyl) substituted 6-[1-(3,5-dimethylphenyl)vinyl]-5-ethyl-1H-pyrimidine-2,4-dione (5b, 16, and 18) showed activities against HIV-1 wild type in the range of Efavirenz, and moderate activities against Y181C and Y181C+K103N mutant strains were also observed.     

Synthesis and structure-activity relationships of M(2)-selective muscarinic receptor ligands in the 1-[4-(4-arylsulfonyl)-phenylmethyl]-4-(4-piperidinyl)-piperazine family

The synthesis and muscarinic binding properties of compounds based on the 1-[4-(4-arylsulfonyl)phenylmethyl]-4-(1-aroyl-4-piperidinyl)-piperazine skeleton are described. For compounds, substituted with appropriately configured methyl groups at the benzylic center and at the piperazine 2-position, high levels of selective, M(2) subtype affinity could be obtained, particularly when the terminal N-aroyl residue was ortho-substituted.     

Design,synthesis and anti-HIV-1 RT evaluation of 2-(benzyl(4-chlorophenyl)amino)-1-(piperazin-1-yl)ethanone derivatives

In this study, using molecular hybridization approach, fourteen novel 2-(benzyl(4-chlorophenyl)amino)-1-(piperazin-1-yl)ethanone derivatives (7a–n) were designed as inhibitor of HIV-1 RT. The binding affinity of the designed compounds with HIV-1 RT as well as their drug-likeness behavior was predicted using in-silico studies. All the designed compounds were synthesized, characterized and in-vitro evaluated for HIV-1 RT inhibitory activity, in which tested compounds displayed significant to weak potency against the selected target. Moreover, best active compounds of the series, 7k and 7m inhibited the activity of RT with IC₅₀ values 14.18 and 12.26 μM respectively. Structure Activity Relationship (SAR) studies were also performed in order to predict the influence of substitution pattern on the RT inhibitory potency. Anti-HIV-1 and cytotoxicity studies of best five RT inhibitor (7a, 7d, 7k, 7L and 7m) revealed that, except compound 7d other compounds retained significant anti-HIV-1 potency with good safety index. Best scoring pose of compound 7m was analysed in order to predict its putative binding mode with wild HIV-1 RT.     

Synthesis of 2-(aminocarbonylmethylthio)-1H-imidazoles as novel Capravirine analogues

Different analogues of Capravirine (AG-1549) or S-1153 were prepared by synthesis of 2-(5-benzyl-4-isopropyl-1-methyl-2,3-dihydro-1H-imidazol-2-ylthio)acetamide (3a-c), ethyl [5-benzyl-1-(ethoxymethyl)-4-ethyl-1H-imidazol-2-ylthio]acetate (10), 2-[5-alkyl-4-substituted 1-(pyridin-4-ylmethyl)-1H-imidazol-2-ylthio]acetamides (12a-f), and 2-[5-benzyl-1-(benzyloxymethyl)-4-isopropyl-1H-imidazol-2-ylthio]acetamides (14a-l) from their corresponding amino acids through a sequence of reactions: Dakin-West reaction, hydrolysis, condensation with thiocyanate derivatives, alkylation with 2-iodoacetamide and ethyl chloroacetate, and coupling with 4-pyridylmethyl chloride, ethoxymethyl chloride and benzyloxymethyl chloride. All the synthesized compounds were screened for their activity against HIV-1 (wild type) and some of them (especially Capravirine like structures) were found active.     

Synthesis and Antitumor Activity of 2-Alkanesulfinyl (or Alkanesulfonyl)-7-methyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-ones

The repressing effect on the propagation of cultured Ehrlich ascites tumor cells by 1, 3, 4-thiadiazolo [3, 2-a] pyrimidine and s-triazolo [1, 5-a] pyrimidine derivatives was examined. Then the relationship between structure and activity as to a series of active compounds was discussed.

The results showed that substituent groups on the 2-position of 1, 3, 4-thiadiazolo [3, 2-a]-pyrimidine took an important part to reveal the cytotoxic activity. Especially, the strong activity was found among the compounds which had electrophilic substituents such as alkylsulfoxide, alkylsulfone at the 2-position.     

Small molecule fusion inhibitors: Design,synthesis and biological evaluation of (Z)-3-(5-(3-benzyl-4-oxo-2-thioxothiazolidinylidene)methyl)-N-(3-carboxy-4-hydroxy)phenyl-2,5-dimethylpyrroles and related derivatives targeting HIV-1 gp41

By a scaffold elongation strategy, a series of (Z)-3-(5-(3-benzyl-4-oxo-2-thioxothiazolidinylidene)methyl)-N-(3-carboxy-4-hydroxy)phenyl-2,5-dimethylpyrroles and related derivatives with a linear multi-aromatic-ring skeleton were designed, synthesized, and evaluated in HIV-1 gp41 and cellular assays. Among them, the most active compounds, 12e, 12g, and 12k with a one-carbon linker (n = 1) between the rhodanine (C) and phenyl (D) rings, exhibited very promising inhibitory potency with IC₅₀ values of 1.8–2.6 μM and EC₅₀ values of 0.3–1.5 μM against gp41 6-HB formation and HIV-1 replication in MT-2 cells, respectively. Additionally, they were almost equally effective against both T20-sensitive and resistant strains. The related SAR studies and molecular modeling results provided potential for further developing a new class of non-peptide small molecular fusion inhibitors targeting the HIV-1 gp41.     

Synthesis and structure-activity relationship of novel diarylpyrimidines with hydromethyl linker (CH(OH)-DAPYs) as HIV-1 NNRTIs

A series of 26 diarylpyrimidines, characterized by the hydroxymethyl linker between the left wing benzene ring and the central pyrimidine, were synthesized and evaluated for in vitro anti-HIV activity. Most of the compounds exhibited moderate to excellent activities against wild-type HIV-1. Among them, compound 10i, bearing a chlorine atom at the C-2 position of left benzene ring, was the best congener and showed potent activity against wild-type HIV-1 with an EC(50) value of 0.009 μM, along with moderate activities against the double RT mutant (K103N+Y181C) HIV-1(III(B)) and HIV-2(ROD) with an EC(50) value of 6.2 and 6.0 μM, respectively. The preliminary structure-activity relationship (SAR) of this new series of compounds was also investigated.     

Diaryldimethylpiperazine ligands with mu- and delta-opioid receptor affinity: Synthesis of (+)-4-[(alphaR)-alpha-(4-allyl-(2S,5S)-dimethylpiperazin-1-yl)-(3-hydroxyphenyl)methyl]-N-ethyl-N-phenylbenzamide and (-)-4-[(alphaR)-alpha-(2S,5S)-dimethylpiperazin-1-yl)-(3-hydroxyphenyl)methyl]-N-ethyl-N-phenylbenzamide

We have explored the synthesis of compounds that have good affinity for both mu- and delta-opioid receptors from the (alphaR,2S,5S) class of diaryldimethylpiperazines. These non-selective compounds were related to opioids that have been found to interact selectively with mu- or delta-opioid receptors as agonists or antagonists. In our initial survey, we found two compounds, (+)-4-[(alphaR)-alpha-(4-allyl-(2S,5S)-dimethylpiperazin-1-yl)-(3-hydroxyphenyl)methyl]-N-ethyl-N-phenylbenzamide (14) and its N-H relative, (-)-4-[(alphaR)-alpha-(2S,5S)-dimethylpiperazin-1-yl)-(3-hydroxyphenyl)methyl]-N-ethyl-N-phenylbenzamide (15), that interacted with delta-receptors with good affinity, and, as we hoped, with much higher affinity at mu-receptors than SNC80. The relative configuration of the benzylic position in (+)-4-[(alphaR)-alpha-(4-allyl-(2S,5S)-dimethyl-1-piperazinyl)-(3-methoxyphenyl)methyl]-benzyl alcohol (10) was determined by X-ray crystallographic analysis of a crystal that was an unresolved twin. The absolute stereochemistry of that benzylic stereogenic center was unequivocally derived by the X-ray crystallographic analysis from the two other centers of asymmetry in the molecule that were known. Those were established from the synthesis via a dipeptide cyclo-L-Ala-L-Ala in which the absolute stereochemistry was established.     

Synthesis and study of anti-HIV-1 RT activity of 5-benzoyl-4-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one derivatives

In the present study, a series of fourteen 5-benzoyl-4-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one derivatives were designed, synthesized and characterized by appropriate spectral analysis. Further, titled compounds were in-vitro screened against wild HIV-1 RT enzyme using ELISA based colorimetric assay, in which four compounds significantly inhibited the RT activity with IC₅₀ ≤ 25 µM. Moreover, two significantly active compounds of the series, A10 and A11 exhibited IC₅₀ values 8.62 and 6.87 µM respectively, during the in-vitro assay. Structure Activity Relationship (SAR) studies were performed for the synthesized compounds in order to estimate the effect of substitution pattern on the RT inhibitory potency. The cytotoxicity of the synthesized compounds was evaluated against T lymphocytes. Further, putative binding modes of the significantly active (A11) and the least active (A4) compounds with wild HIV-1 RT were also investigated using docking studies.     

Synthesis and biological evaluation of novel 6-substituted 5-alkyl-2-(arylcarbonylmethylthio)pyrimidin-4(3H)-ones as potent non-nucleoside HIV-1 reverse transcriptase inhibitors

A novel series of 2-arylcarbonylmethylthio-6-arylmethylpyrimidin-4(3H)-ones have been synthesized and evaluated for in vitro anti-HIV activities in MT-4 cells. Most of these new compounds showed moderate to potent activities against wild-type HIV-1 with an EC(50) range from 8.97 microM to 0.010 microM. Among them, the 6-(3,5-dimethylbenzyl) analogue 5p was identified as the most promising compound (EC(50)=0.010 microM, SI>31,800) associated with moderate activity against the HIV-1 double mutant RT strain K103N+Y181C. The structure-activity relationships of these new congeners were further discussed.     

Synthesis,cyclooxygenase inhibitory effects,and molecular modeling study of 4-aryl-5-(4-(methylsulfonyl)phenyl)-2-alkylthio and -2-alkylsulfonyl-1H-imidazole derivatives

A series of 4-aryl-5-(4-(methylsulfonyl)phenyl)-2-alkylthio and 2-alkylsulfonyl-1H-imidazole derivatives were synthesized. All compounds were tested in human blood assay to determine COX-1 and COX-2 inhibitory potency and selectivity. Among the synthesized compounds, 2-alkylthio series were more potent and selective than 2-sulfonylalkyl derivatives. In molecular modeling, interaction of 2-sulfonylalkyl moiety with Arg120 in COX-1 and an extra hydrogen bond with Tyr341 in COX-2 increased the residence time of ligands in the active site in 2-sulfonylalkyl and 2-alkylthio analogs, respectively.     

N-[2-(1-cyclohexenyl)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea and N'-[2-(1-cyclohexenyl)ethyl]-N'-[2-(5-chloropyridyl)]-thiourea as potent inhibitors of multidrug-resistant human immunodeficiency virus-1.

We have replaced the pyridyl ring of trovirdine with an alicyclic cyclohexenyl, adamantyl or cis-myrtanyl ring. Only the cyclohexenyl-containing thiourea compound N-[2-(1-cyclohexenyl)ethyl]-N'-[2-(5-bromopyridyl)]- thiourea (HI-346) (as well as its chlorine-substituted derivative N-[2-(1-cyclohexenyl)ethyl]-N'-[2-(5-chloropyridyl)]- thiourea/HI-445) showed RT inhibitory activity. HI-346 and HI-445 effectively inhibited recombinant RT with better IC50 values than other anti-HIV agents tested. The ranking order of efficacy in cell-free RT inhibition assays was: HI-346 (IC50 = 0.4 microM) > HI-445 (IC50 = 0.5 microM) > trovirdine (IC50 = 0.8 microM) > MKC-442 (IC5 = 0.8 microM) = delavirdine (IC50 = 1.5 microM) > nevirapine (IC50 = 23 microM). In accord with this data, both compounds inhibited the replication of the drug-sensitive HIV-1 strain HTLV(IIIB) with better IC50 values than other anti-HIV agents tested. The ranking order of efficacy in cellular HIV-1 inhibition assays was: HI-445 = HI-346 (IC50 = 3 nM) > MKC-442 (IC50 = 4 nM) = AZT (IC50 = 4 nM) > trovirdine (IC50 = 7 nM) > delavirdine (IC50 = 9 nM) > nevirapine (IC50 = 34 nM). Surprisingly, the lead compounds HI-346 and HI-445 were 3-times more effective against the multidrug resistant HIV-1 strain RT-MDR with a V106A mutation (as well as additional mutations involving the RT residues 74V,41L, and 215Y) than they were against HTLV(IIIB) with wild-type RT. HI-346 and HI-445 were 20-times more potent than trovirdine, 200-times more potent than AZT, 300-times more potent than MKC-442, 400-times more potent than delavirdine, and 5000-times more potent than nevirapine against the multidrug resistant HIV-1 strain RT-MDR. HI-445 was also tested against the RT Y181C mutant A17 strain of HIV-1 and found to be >7-fold more effective than trovirdine and >1,400-fold more effective than nevirapine or delavirdine. Similarly, both HI-346 and HI-445 were more effective than trovirdine, nevirapine, and delavirdine against the problematic NNI-resistant HIV-1 strain A17-variant with both Y181C and K103N mutations in RT, although their activity was markedly reduced against this strain. Neither compound exhibited significant cytotoxicity at effective concentrations (CC50 >100 microM). These findings establish the lead compounds HI-346 and HI-445 as potent inhibitors of drug-sensitive as well as multidrug-resistant stains of HIV-1.     

Synthesis and antitubercular activity of 7-(R)- and 7-(S)-methyl-2-nitro-6-(S)-(4-(trifluoromethoxy)benzyloxy)-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazines, analogues of PA-824

Nitroimidazoles such as PA-824 and OPC-67683 are currently in clinical development as members of a promising new class of therapeutics for tuberculosis. While the antitubercular activity of these compounds is high, they both suffer from poor water solubility thus complicating development. We determined the single crystal X-ray structure of PA-824 and found a close packing of the nitroimidazoles facilitated by a pseudoaxial conformation of the p-trifluoromethoxybenzyl ether. To attempt to disrupt this tight packing by destabilizing the axial preference of this side chain, we prepared the two diastereomers of the 7-methyl-nitroimidazo-oxazine. Determination of the crystal structure of the 7-(S)-methyl derivative (5, cis) revealed that the benzylic side chain remained pseudoaxial while the 7-(R)-methyl derivative (6, trans) adopted the desired pseudoequatorial conformation. Both derivatives displayed similar activities against Mycobacterium tuberculosis, but neither showed improved aqueous solubility, suggesting that inherent lattice stability is not likely to be a major factor in limiting solubility. Conformational analysis revealed that all three compounds have similar energetically accessible conformations in solution. Additionally, these results suggest that the nitroreductase that initially recognizes PA-824 is somewhat insensitive to substitutions at the 7-position.