Salvador Vega

Synthesis and anti-HIV activity of 1,1,3-trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazines (TTDs): a new family of HIV-1 specific non-nucleoside reverse transcriptase inhibitors

The anti-HIV activity of a novel series of 1,1,3-trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazines (TTDs) has been described. The compounds were synthesized via Curtius rearrangement of appropriate sulfamoylcarboxy azides which, in turn, were prepared from known starting materials. Several 4-substituted-2-benzyl-derivatives were found to selectively inhibit human immunodeficiency virus type 1 [HIV-1 (IIIB)] replication in MT-4 and CEM cells. These TTDs were also effective against other strains of HIV-1 (RF, HE, MN, NDK), including those that are resistant to AZT, but not against HIV-2 (ROD) or simian immunodeficiency virus [SIV(MAC251)] at subtoxic concentrations. Some of the test compounds exhibited antiviral activity against L100I RT mutant virus, but significantly lost antiviral activity against K103N, V106A, E138K, Y181C and Y188H RT mutant viruses. Compounds 6d, 6f and 6g were inhibitory to HIV-1 RT at concentrations that rank between 16.4 and 59.8 microM (nevirapine: IC50 = 4.5 microM against HIV-1 RT). Inhibition of HIV-1 RT by compound 6g was purely non-competitive with respect to the natural substrate (dGTP), which is in agreement with the nature of inhibition shown by other NNRTIs such as nevirapine and delarvidine. A structure-activity relationship was established for the anti-HIV activity of these heterocyclic compounds. TTDs represent a new chemical class of non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs).

Thiophene isosteres: synthesis and pharmacological study of 3-(azol-1-yl)thieno isothiazole-1,1-dioxides

Abstract Three series of new 3-(azol-1-yl)thieno isothiazole-1,1-dioxides were synthesized and tested for anti-inflammatory and related pharmacological activities as well as for acute toxicity. Acetylsalicylic acid was used as the reference standard.

Synthesis and pharmacological evaluationof 2,3-dihydro-3-oxo-4H-thieno[3,4-e][1,2,4]thiadiazine 1,1-dioxidesas voltage-dependent calcium channel blockers

The synthesis of a novel series of 2,3-dihydro-3-oxo-4H-thieno[3, 4-e][1,2,4]thiadiazine 1,1-dioxides and their pharmacological evaluation as drugs with effects on the rat cardiovascular system are described. The compounds under study were synthesized via Curtius rearrangement of appropriate sulfamoylacylazides which, in turn, were prepared from known starting materials. In isolated rat portal vein, these thienothiadiazines, like verapamil and diazoxide, inhibited the spontaneous motility produced by KCl (20 mM). In addition, the new compounds, like verapamil and unlike diazoxide, also exhibited inhibitory effects in the same preparation when the cell membrane was depolarized by an increased extracellular KCl concentration (80 mM) and, consequently, the membrane potential approached a level close to the K(+) equilibrium potential. Further characterization of this inhibitory activity led to the identification of a selective inhibitory effect of the new compounds on KCl (80 mM)-induced 45Ca(2+) uptake in the same vascular tissue. When tested in vivo (anaesthetized normotensive rats), acute administration of verapamil, diazoxide and some of the most in vitro potent compounds in 45Ca(2+) uptake experiments produced a gradual, dose-dependent and sustained decrease in diastolic arterial blood pressure, devoid of cardiac effects. These results suggest that, like verapamil, the cardiovascular effects produced by the new thienothiadiazines seem to be due, at least in part, to a blockade of transmembrane voltage-dependent calcium channels present in vascular smooth muscle cells and not to an activation of ATP-sensitive K(+) channels. Compounds 5b, 5e and 5i have been selected for further studies as antihypertensive agents.

Thiophene isosteres: synthesis and biological evaluation of 3-substituted derivatives of 4-phenyl-2-thioxo-benzo[4,5] thieno[2,3-d]pyrimidine

Abstract As an extension of a previous work, in which a series of 4-phenyl-2-thioxo-benzo[4,5]thieno[2,3-d]pyrimidines were synthesized, a new series of 3-amino derivatives of this ring system has been prepared. The products obtained together with those reported in the previous paper, were tested for analgesic, antipyretic and anti-inflammatory activities as well as for acute toxicity. Since these compounds could be useful for the treatment of neoplasms, their cytostatic activity was also investigated.

5,6-Dihydro-1H,4H-pyrazolo[4,3-f]pyrrolo[1,2-a][1,4]diazepines. Synthesis and pharmacological evaluation

Abstract A series of new 5,6 dihydro-1H,4H-pyrazolo[4,3-f]pyrrolo[1,2-a][1,4]diazepines was synthesized and tested for acute toxicity and CNS activity in mice. Some of these compounds were shown to possess anxiolytic activity similar to that of diazepam, with weak anticonvulsant and sedative action.

Synthesis and Anti‐HIV Activity Evaluation of Novel 2,4‐Disubstituted 7‐Methyl‐1,1,3‐trioxo‐2,4‐dihydro‐pyrazolo‐[4,5‐e][1,2]thiadiazines

A series of novel 2,4‐disubstituted 7‐methyl‐1,1,3‐trioxo‐2,4‐dihydro‐pyrazolo[4,5‐e] [1,2,4]thiadiazines (PTDs) was synthesized, structurally confirmed by spectral analysis, and evaluated for their anti‐HIV activities by inhibition of HIV‐induced cytopathogenicity in MT‐4 cell culture. The results showed that some compounds exhibited inhibitory activity specifically against HIV‐2 replication. The most active HIV‐2 inhibitor was compound 7i (R1 = benzyl, R2 = 4‐t‐butyl‐benzyl) with an EC50 value of 18.7 μM and SI=15, which may provide a useful lead for further molecular optimization.

Regioselective Synthesis of Novel N2- and N4-Substituted 7-Methylpyrazolo[4,5-e][1,2,4]thiadiazines

The new compound 7-methylpyrazolo[4,5-e][1,2,4]thiadiazin-3(2H,4H)-one1,1-dioxide (5) was synthesized and its novel mono N2- or N4-substituted derivatives 6 and 7 were prepared by regioselective N-alkylation of 5 with different molar ratios of NaH and alkyl halides. Based on the regioselective alkylation conditions found a facile one-pot synthesis of N2,N4-disubstituted pyrazolo[4,5-e][1,2,4] thiadiazines 8 was developed. The structures of the newly synthesized compounds were confirmed by IR,(1)H-NMR, (13)C-NMR and MS spectral analysis.