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.     

Inhibition of mast cell leukotriene release by thiourea derivatives

Mast cell derived leukotrienes (LT's) play a vital role in pathophysiology of allergy and asthma. We synthesized various analogues of indolyl, naphthyl and phenylethyl substituted halopyridyl, thiazolyl and benzothiazolyl thioureas and examined their in vitro effects on the high affinity IgE receptor/FcERI-mediated mast cell leukotriene release. Of the 22 naphthylethyl thiourea compounds tested, there were seven active compounds and N-[1-(1-naphthyl)ethyl]-N'-[2-(ethyl-4-acetylthiazolyl)]thiourea (17 and 16) (IC(50)=0.002 microM) and N-[1-(1R)-naphthylethyl]-N'-[2-(5-methylpyridyl)]thiourea (5) (IC(50)=0.005 microM) were identified as the lead compounds. Among the 11 indolylethyl thiourea compounds tested, there were seven active compounds and the halopyridyl compounds N-[2-(3-indolylethyl)]-N'-[2-(5-chloropyridyl)]thiourea and N-[2-(3-indolylethyl)]-N'-[2-(5-bromopyridyl)]thiourea were the most active agents and inhibited the LTC(4) release with low micromolar IC(50) values of 4.9 microM and 6.1 microM, respectively. The hydroxylphenyl substituted compounds N-[2-(4-hydroxyphenyl)ethyl]-N'-[2-(5-chloropyridyl)]thiourea (IC(50)=12.6 microM), N-[2-(4-hydroxyphenyl)ethyl]-N'-[2-(5-bromopyridyl)]thiourea (IC(50)=16.8 microM) and N-[2-(4-hydroxyphenyl)ethyl]-N'-[2-(pyridyl)]thiourea (IC(50)=8.5 microM) were the most active pyridyl thiourea agents. Notably, the introduction of electron withdrawing or donating groups had a marked impact on the biological activity of these thiourea derivatives and the Hammett sigma values of their substituents were identified as predictors of their potency. In contrast, experimentally determined partition coefficient values did not correlate with the biological activity of the thiourea compounds which demonstrates that their liphophilicity is not an important factor controlling their mast cell inhibitory effects.     

Substituted heterocyclic thiourea compounds as a new class of anti-allergic agents inhibiting IgE/Fc epsilon RI receptor mediated mast cell leukotriene release

Mast cell derived leukotrienes (LT's) play a vital role in pathophysiology of allergy and asthma. We synthesized various analogues of indolyl, naphthyl and phenylethyl substituted halopyridyl, thiazolyl and benzothiazolyl thioureas and examined their in vitro effects on the high affinity IgE receptor/Fc epsilon RI-mediated mast cell leukotriene release. Of the 22 naphthylethyl thiourea compounds tested, there were 7 active compounds and N-[1-(1-naphthyl)ethyl]-N'-[2-(ethyl-4-acetylthiazolyl)]thiourea (17 and 16) (IC(50)=0.002 microM) and N-[1-(1R)-naphthylethyl]-N'-[2-(5-methylpyridyl)]thiourea (compound 5) (IC(50)=0.005 microM) were identified as the lead compounds. Among the 11 indolylethyl thiourea compounds tested, there were seven active compounds and the halopyridyl compounds N-[2-(3-indolylethyl)]-N'-[2-(5-chloropyridyl)]thiourea (24) and N-[2-(3-indolylethyl)]-N'-[2-(5-bromopyridyl)]thiourea (25) were the most active agents and inhibited the LTC(4) release with low micromolar IC(50) values of 4.9 and 6.1 microM, respectively. The hydroxylphenyl substituted compounds N-[2-(4-hydroxyphenyl)ethyl]-N'-[2-(5-chloropyridyl)]thiourea (37; IC(50)=12.6 microM), N-[2-(4-hydroxyphenyl)ethyl]-N'-[2-(5-bromopyridyl)]thiourea (50; IC(50)=16.8 microM) and N-[2-(4-hydroxyphenyl)ethyl]-N'-[2-(pyridyl)]thiourea (35; IC(50)=8.5 microM) were the most active pyridyl thiourea agents. Notably, the introduction of electron withdrawing or donating groups had a marked impact on the biological activity of these thiourea derivatives and the Hammett sigma values of their substituents were identified as predictors of their potency. In contrast, experimentally determined partition coefficient values did not correlate with the biological activity of the thiourea compounds which demonstrates that their liphophilicity is not an important factor controlling their mast cell inhibitory effects. These results establish the substituted halopyridyl, indolyl and naphthyl thiourea compounds as a new chemical class of anti-allergic agents inhibiting IgE receptor/Fc epsilon RI-mediated mast cell LTC(4) release. Further lead optimization efforts may provide the basis for new and effective treatment as well as prevention programs for allergic asthma in clinical settings.     

N'-[2-(2-thiophene)ethyl]-N'-[2-(5-bromopyridyl)] thiourea as a potent inhibitor of NNI-resistant and multidrug-resistant human immunodeficiency virus-1

The thiophene-ethyl thiourea (TET) compound N′-[2-(2-thiophene)ethyl]-N′-[2-(5-bromopyridyl)]-thiourea (compound HI-443) was five times more potent than trovirdine, 1250 times more potent than nevirapine, 100 times more potent than delavirdine, 75 times more potent than MKC-442, and 50 times more potent than AZT against the multidrug resistant HIV-1 strain RT-MDR with a V106A mutation. HI-443 was almost as potent against the NNI-resistant HIV-1 strain A17 with a Y181C mutation as it was against HTLV_IIIB. The activity of HI-443 against A17 was ten times more potent than that of trovirdine, 2083 times more potent than that of nevirapine, and 1042 times more potent than that of delavirdine. HI-443 inhibited the replication of the NNI-resistant HIV-1 strain A17 variant with Y181C plus K103N mutations in RT with an IC₅₀ value of 3.3 μM, whereas the IC₅₀ values of trovirdine, nevirapine, and delavirdine were all >100 μM. These findings establish the novel thiophene containing thiourea compound HI-443 as a novel NNI with potent antiviral activity against NNI-sensitive, NNI-resistant and multidrug-resistant strains of HIV-1.     

Synthesis of 5-alkenylated D4T analogues via the Pd-catalyzed cross-coupling reaction

The target compounds 5-[N-(6-amino-hexyl)-acrylamide]-2',3'-didehydro-2',3'-dideoxy-uridine (12) and 5-[N-[5-(methoxycarbonyl)-pentyl]-acrylamide]-2',3'-didehydro-2',3'- dideoxy-uridine (15) were prepared by the palladium acetate-triphenylphosphine-catalyzed reaction of the 5'-O-acetyl-5-iodo-d4T analogue (3). These compounds 12 and 15 can be used to prepare nucleotide probes carrying fluorescent labels and were nevertheless screened for their anti-HIV activity. The biological data demonstrated that none of them were active against HIV-1.     

Synthesis of N-substituted 9-azabicyclo[3.3.1]nonan-3alpha-yl carbamate analogs as sigma2 receptor ligands

A series of N-substituted 9-azabicyclo[3.3.1]nonan-3alpha-yl phenylcarbamate analogs was prepared and their affinities for sigma (sigma(1) and sigma(2)) receptors were measured in vitro. The results of their structure-activity relationship study identified two new compounds, N-(9-(4-aminobutyl)-9-azabicyclo[3.3.1]nonan-3alpha-yl)-N'-(2-methoxy-5-methylphenyl)carbamate and N-(9-(6-aminohexyl)-9-azabicyclo[3.3.1]nonan-3alpha-yl)-N'-(2-methoxy-5-methylphenyl)carbamate, having a high affinity and selectivity for sigma(2) versus sigma(1) receptors. These compounds were also used in the preparation of biotinylated and fluorescent probes of the sigma(2) receptor.     

Analysis of structure-activity relationships for the 'B-region' of N-(4-t-butylbenzyl)-N'-[4-(methylsulfonylamino)benzyl]-thiourea analogues as TRPV1 antagonists

The structure-activity relationships for the 'B-region' of N-(4-t-butylbenzyl)-N'-[4-(methylsulfonylamino)benzyl]thiourea analogues have been investigated as TRPV1 receptor antagonists. A docking model of potent antagonist 2 with the sensor region of TRPV1 is proposed.     

Alpha-substituted N-(4-tert-butylbenzyl)-N'-[4-(methylsulfonylamino)benzyl]thiourea analogues as potent and stereospecific TRPV1 antagonists

A series of alpha-substituted N-(4-tert-butylbenzyl)-N'-[4-(methylsulfonylamino)benzyl]thiourea analogues have been investigated as TRPV1 receptor antagonists. alpha-Methyl substituted analogues showed potent and stereospecific antagonism to the action of capsaicin on rat TRPV1 heterologously expressed in Chinese hamster ovary cells. In particular, compounds 14 and 18, which possess the R-configuration, exhibited excellent potencies (respectively, K(i)=41 and 39.2 nM and K(i(ant))=4.5 and 37 nM).     

Novel N-3 substituted TSAO-T derivatives: synthesis and anti-HIV-evaluation

Novel derivatives of the anti-HIV-1 agent, TSAO-T, bearing at the N-3 position alkylating groups or photoaffinity labels were prepared and evaluated for their anti-HIV activity. All of these compounds demonstrated pronounced anti-HIV-1 activity and inhibited HIV-1 RT; however, we were unable to detect stable covalent linkages between inhibitor and enzyme. In addition, compounds with an alcohol functional group connected to the N-3 position through a cis or trans double bond have been prepared. These compounds have been useful to study how the conformational restriction of the linker affects in the interaction between the N-3 substituent and the HIV-1 RT enzyme.     

Predicting anti-HIV activity of PETT derivatives: CoMFA approach

HIV-1 (Human Immunodeficiency Virus Type-1) is the pathogenic retrovirus and causative agent of AIDS. HIV-1 RT is one of the key enzymes in the duplication of HIV-1. Inhibitors of HIV-1 RT are classified as NNRTIs and NRTIs. NNRTIs bind in a region not associated with the active site of the enzyme. Within the NNRTIs category, there is a set of inhibitors commonly referred to as phenyl ethyl thiazolyl thiourea (PETT) derivatives. The present 3D QSAR study attempts to explore the structural requirements of phenyl ethyl thiazolyl thiourea (PETT) derivatives for anti-HIV activity. Based on the structures and biodata of previous PETT analogs, 3D-QSAR (CoMFA) study has been performed with a training set consisting of 60 molecules, which resulted in a reliable computational model with q(2)=0.657, S(PRESS)=0.957, r(2)=0.938, and standard error of estimation (SEE)=0.270 with the number of partial least square (PLS) components being 5. It is shown that the steric and electrostatic properties predicted by CoMFA contours can be related to the anti-HIV activity. The predictive ability of the resultant model was evaluated using a test set comprised of 11 molecules and the predicted r(2)=0.893. This model is a more significant guide to trace the features that really matter especially with respect to the design of novel compounds.