Structure-based design, synthesis, and biological evaluation of novel pyrrolyl aryl sulfones: HIV-1 non-nucleoside reverse transcriptase inhibitors active at nanomolar concentrations.

Pyrrolyl aryl sulfones (PASs) have been recently reported as a new class of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) inhibitors acting at the non-nucleoside binding site of this enzyme (Artico, M.; et al. J. Med. Chem. 1996, 39, 522-530). Compound 3, the most potent inhibitor within the series (EC(50) = 0.14 microM, IC(50) = 0.4 microM, and SI > 1429), was then selected as a lead compound for a synthetic project based on molecular modeling studies. Using the three-dimensional structure of RT cocrystallized with the alpha-APA derivative R95845, we derived a model of the RT/3 complex by taking into account previously developed structure-activity relationships. Inspection of this model and docking calculations on virtual compounds prompted the design of novel PAS derivatives and related analogues. Our computational approach proved to be effective in making qualitative predictions, that is in discriminating active versus inactive compounds. Among the compounds synthesized and tested, 20 was the most active one, with EC(50) = 0.045 microM, IC(50) = 0.05 microM, and SI = 5333. Compared with the lead 3, these values represent a 3- and 8-fold improvement in the cell-based and enzyme assays, respectively, together with the highest selectivity achieved so far in the PAS series.

5H-pyrrolo[1,2-b] [1,2,5]benzothiadiazepines (PBTDs): a novel class of non-nucleoside reverse transcriptase inhibitors.

With the aim of developing novel inhibitors of human immunodeficiency virus, various derivatives (10-17) related to 5H-pyrrolo[1,2-b] [1,2,5]benzothiadiazepine (PBTD) were prepared and tested in vitro. The title tricyclic derivatives were obtained by intramolecular cyclization of the open-chain intermediate arylpyrrylsulfones, followed by N-alkylation at position 10. Among test derivatives some 10-alkyl-5H-pyrrolo[1,2-b] [1,2,5]benzothiadiazepin-11(10H)-one-5,5-dioxides were found to exert potent and specific activity against HIV-1. In particular, 7-chloro derivatives 11i and j showed a potency comparable to that of nevirapine. However, when the chloro atom was shifted to the 8 position, the related products were scarcely active or totally inactive. Replacement of the pyrrole with pyrrolidine led to inactive products and the reduction of SO2 to S strongly diminished the antiviral potency. PBTD derivatives active in cell cultures were also inhibitory to the recombinant HIV-1 RT in enzyme assays, thus allowing the conclusion that PBTDs are a new class of non-nucleoside reverse transcriptase inhibitors (NNRTIs).

Synthesis and anti-HIV activity of 10,11-dihydropyrrolo [1,2-b][1,2,5]benzothiadiazepine-11-acetic acid 5,5-dioxide derivatives and related compounds.

The synthesis and the in vitro anti-HIV-1 activity of novel pyrrolo annulated benzothiadiazepine acetic acids and some related derivatives are reported. The new compounds share chemical features with pyrrolo[1,2-d][1,4]benzodiazepin-6-one 1 and Ro 5-3335 pyrrylbenzodiazepinone 4, two inhibitors of HIV-replication at the level of reverse transcriptase (RT) and transcriptional transactivation by Tat, respectively. Two derivatives, namely methyl 10,11-dihydropyrrolo[1,2-b][1,2,5]benzothiadiazepine-11-acetic-5,5 -dioxide (5a) and 1,12b-dihydro-2H-azeto[2,1-d]pyrrolo[1,2-b][1,2,5]benzoth iadiazepin-2-one 8,8-dioxide (7a), were found to exhibit a significant, although not very potent, activity against human immunodeficiency virus Type 1 (HIV-1).

Antifungal agents. 10. Synthesis and antifungal activities of aryl-(1H-imidazol-1-yl)-(isoquinolin-1-yl) methane derivatives.

Various aryl-(1H-imidazol-1-yl)-(isoquinolin-1-yl)methane derivatives have been synthesized and tested as antifungal agents. The new imidazoles have been obtained by the action of 1,1'-sulfinyldiimidazole on aryl-(isoquinolin-1-yl)carbinols, which have been prepared by standard procedures starting from isoquinoline. Among 44 test derivatives only a few have exhibited some antifungal activity, the most active compound (4e) being twofold less potent than miconazole, ketoconazole and bifonazole, used as standard drugs.

Synthesis of pyrryl aryl sulfones targeted at the HIV-1 reverse transcriptase.

Various aryl 1-pyrryl sulfones were synthesized and tested as inhibitors of HIV-1. 2-Nitrophenyl-2-ethoxycarbonyl-1-pyrryl sulfone, the most active among test derivatives, was selected as lead compound of the aryl pyrryl sulfone series. The in vitro anti-HIV-1 activity and cytotoxicity of 41 compounds is reported. Some structure-activity relationships are discussed also in comparison with the known NPPS (2-nitrophenyl phenyl sulfone).

Non-steroidal antiinflammatory agents. Synthesis and enzyme inhibition of 2-[4-(heteroarylmethyl)phenyl] propanoic acids and analogues.

Some 2-[4-(heteroarylmethyl)phenyl]propanoic acids and phenylacetic and benzoic analogues has been synthesized. All above acids were tested for their inhibitory activity on lipoxygenase and cyclooxygenase, in comparison with NDGA and tolmetin. 2-[4-(Thien-2-ylmethyl)phenyl]propanoic acid 2, strictly related with suprofen, was found the most interesting compound, giving rise to a 79% inhibition of the cyclooxygenase activity at 10(-4) M concentration.

Antifungal agents. VI. In vitro antifungal activities of halobenzoyl esters of cis- and trans-[2-(1,1'-biphenyl-4-yl)-2-(1H-imidazol-1-ylmethyl)-1,3- dioxolan-4-yl]carbinols.

The synthesis and the in vitro antifungal activities against Candida albicans and Candida spp of a number of halobenzoyl esters of cis- and trans- [2-(1,1'-biphenyl-4-yl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan -4- yl]carbinols is reported. Some new imidazoles were found more active than ketoconazole and sometimes as potent as bifonazole against Candida albicans. All derivatives were found scarcely active against Candida spp.