Marino Artico

Antimycobacterial pyrroles: synthesis, anti-Mycobacterium tuberculosis activity and QSAR studies

A number of known antifungal pyrrole derivatives and some newly synthesized compounds (5-33) were tested in vitro against Mycobacterium tuberculosis CIP 103471. The majority of tested compounds were efficient antimycobacterial agents showing MIC values ranging from 0.5 to 32 microg/mL. A 3-D-QSAR study has been performed on these pyrrole derivatives to correlate their chemical structures with their observed inhibiting activity against M. tuberculosis. Due to the absence of information on a putative receptor responsible for this activity, classical quantitative structure-activity relationships (QSAR) and comparative molecular field analysis (CoMFA) have been applied. A model able to well correlate the antimycobacterial activity with the chemical structures of pyrrole derivatives 5-33 has been developed which is potentially helpful in the design of novel and more potent antituberculosis agents. The combination of CoMFA with classical QSAR descriptors led to a better hybrid 3-D-QSAR model, that successfully explains the structure-activity relationships (r2 = 0.86) of the training set. A comparison between the QSAR, CoMFA and mixed QSAR-CoMFA models is also presented. The hybrid model is to be preferred, however, because of its lowest values of the average absolute error of prediction toward a limited external test set.

3,4-Dihydro-2-Alkoxy-6-Benzyl-4-Oxopyrimidines (DABOs): A New Class of Specific Inhibitors of Human Immunodeficiency Virus Type 1

A series of novel 3,4-dihydro-6-benzyl-4-oxopyrimidines substituted at both the C-5 and the C-2 positions were synthesized as potential anti-HIV agents. Preparation of the title compounds was achieved by condensation of O-methylisourea with methyl 2-alkyl-4-phenylacetylacetate and subsequent displacement of the methoxy group by reaction with a series of linear, ramified and cyclic alkoxy groups containing from three to six carbon units. Methyl 2-alkyl-4-phenylacetylacetates were prepared by alkylation of methyl 4-phenylacetylacetate, which was obtained starting from Meldrums acid and phenacetyl chloride. Acid hydrolysis of 3,4-dihydro-6-benzyl-2-methoxy-4-oxopyrimidines furnished the corresponding 1,2,3,4-tetrahydro-6-benzyl-2,4-dioxopyrimidines. In acutely infected MT-4 cells, compounds 3e, 3o, 3q and 3r showed an anti-HIV-1 activity as potent and/or selective as HEPT and ddl. Unlike HEPT, the replacement of a methyl for an hydrogen atom at position C-5 of 3,4-dihydro-2-alkoxy-6-benzyl-4-oxopyrimidines (DABOs) did not abolish the antiviral activity, as well as the substitution of the C-5 methyl for an ethyl group did not increase the potency. However, similarly to HEPT and its derivatives, DABOs targeted the HIV-1 reverse transcriptase and neither inhibited the multiplication of HIV-2 in acutely infected MT-4 cells, nor that of HIV-1 in chronically infected H9/IIIB cells.

5-alkyl-6-benzyl-2-(2-oxo-2-phenylethylsulfanyl)pyrimidin-4(3H)-ones, a series of anti-HIV-1 agents of the dihydro-alkoxy-benzyl-oxopyrimidine family with peculiar structure - Activity relationship profile

A series of dihydro-alkylthio-benzyl-oxopyrimidines (S-DABOs) bearing a 2-aryl-2-oxoethylsulfanyl chain at pyrimidine C2, an alkyl group at C5, and a 2,6-dichloro-, 2-chloro-6-fluoro-, and 2,6-difluoro-benzyl substitution at C6 (oxophenethyl- S-DABOs, 6-8) is here described. The new compounds showed low micromolar to low nanomolar (in one case subnanomolar) inhibitory activity against wt HIV-1. Against clinically relevant HIV-1 mutants (K103N, Y181C, and Y188L) as well as in enzyme (wt and K103N, Y181I, and L100I mutated RTs) assays, compounds carrying an ethyl/ iso-propyl group at C5 and a 2,6-dichloro-/2-chloro-6-fluoro-benzyl moiety at C6 were the most potent derivatives, also characterized by low fold resistance ratio. Interestingly, the structure-activity relationship (SAR) data drawn from this DABO series are more related to HEPT than to DABO derivatives. These findings were at least in part rationalized by the description of a fair superimposition between the 6-8 and TNK-651 (a HEPT analogue) binding modes in both WT and Y181C RTs.

Pyrrolnitrin and related pyrroles endowed with antibacterial activities against Mycobacterium tuberculosis

During development of nitroheterocycles with potential antimycobacterial activities we have tested against Mycobacterium tuberculosis a number of pyrroles strictly related to pyrrolnitrin, an antifungal antibiotic isolated from Streptomyces pyrrocinia. Some of the tested arylpyrrole derivatives and pyrrolnitrin have shown appreciable inhibiting activity against M. tuberculosis and M. avium. SAR studies well correlate antimycobacterial potency with the presence of halogens in the phenyl ring and a nitro group at position 3 of pyrrole.

Synthesis and Antiviral Activity of New 3,4-Dihydro-2-Alkoxy-6-Benzyl-4-Oxopyrimidines (DABOs), Specific Inhibitors of Human Immunodeficiency Virus Type 1

3,4-Dihydro-2-alkoxy-6-benzyl-4-oxopyrimidines (DABOs) have emerged as non-nucleoside inhibitors of human immunodeficiency virus type 1 [Artico et al. (1993), Antiviral Chem Chemother 4: 361-368]. With a view to increasing their potency, a new series of DABO derivatives, differently substituted at positions C-2 and/or C-5 of the pyrimidine ring and 3′ or 3′,5′ of the benzyl moiety, have been synthesized. DABOs were prepared by reacting O-methylisourea with the appropriate methyl 2-alkyl-4-phenylacetylacetate, with formation of 3,4-dihydro-2-methoxy-6-arylmethyl-4-oxopyrimidines. Subsequent displacement of the methoxy group linked at the 2-position of the pyrimidine ring by treatment with alkoxy and cycloalkoxy potassium salts led to the required derivatives. In vitro, the most potent compounds were 12e and 12p, which had an EC50 of 0.8 μM and a selective index of 400.

Design, synthesis and QSAR studies on N-aryl heteroarylisopropanolamines, a new class of non-peptidic HIV-1 protease inhibitors.

A series of N-aryl heteroarylisopropanolamines in which an indole or a 3-arylpyrrole moiety was linked to an aryl group through an isopropanolamine linker, were designed and synthesized as potential anti-HIV-1-PR agents. Series was tested for their ability in blocking PR activity. As a rule, indole derivatives of class 1 exhibited more potency than pyrrole analogues of class 2 while tert-butylamide substituents increased anti-PR potency. In fact, bis tert-butylamide 1e showed the highest activity with IC(50)=25 microM. Even if not very potent, a simple class of anti-PR agents, with a facile synthetic pathway was discovered. QSAR studies on isopropanolamines 1 and 2 were performed in comparison with diarylbutanols, a new class of non peptidic anti-PR agents, recently discovered by Agouron Pharmaceuticals. QSAR and CoMFA models based on 30 diarylbutanols used as a training set were developed. The obtained models were used to investigate the binding mode of the newly synthesized derivatives 1 and 2. The results of this study suggest that N-aryl heteroarylisopropanolamines bind to the PR active site similarly to the diarylbutanols of Agouron.

Diarylpyrimidine−Dihydrobenzyloxopyrimidine Hybrids: New, Wide-Spectrum Anti-HIV-1 Agents Active at (Sub)-Nanomolar Level

Here, we describe a novel small series of non-nucleoside reverse transcriptase inhibitors (NNRTIs) that combine peculiar structural features of diarylpyrimidines (DAPYs) and dihydro-alkoxy-benzyl-oxopyrimidines (DABOs). These DAPY-DABO hybrids (1-4) showed a characteristic SAR profile and a nanomolar anti-HIV-1 activity at both enzymatic and cellular level. In particular, the two compounds 4d and 2d, with a (sub)nanomolar activity against wild-type and clinically relevant HIV-1 mutant strains, were selected as lead compounds for next optimization studies.

Synthesis, antimicrobial and antiviral activities of isotrimethoprim and some related derivatives

Abstract The synthesis and the antimicrobial activities of 2,4-diamino-6-(3,4,5-trimethoxybenzyl)pyrimidine (isotrimethoprim) and some related derivatives are reported. The new derivatives have been found scarcely active against bacteria and fungi, with the only exception of 4-chloro-2-methoxypyrimidinyl-3,4,5-trimethoxyphenyldichloromethane, which showed good antibacterial activity against Staphylococcus aureus . Cytotoxicity and antiviral assays, HIV included, have also been determined in comparison with TMP and AZT. Little but selective activity was shown by some derivatives against HIV retrovirus.

Aromatic hydrazides as specific inhibitors of bovine serum amine oxidase

Abstract New hydrazides were synthesized in search for specific inhibitors of bovine serum amine oxidase: a series of benzoic and phenylacetic acid hydrazides containing the 1 H -imidazol-1-yl or the 1 H -imidazol-1-ylmethyl group as ( o, m, p )-substituent in the phenyl ring; an analogous series of p -substituted phenylhydrazides with 5 or 6-membered heterocyclic ring as substituent, and a series of similar phenylpropionic hydrazides. The longer and more flexible phenylacetic hydrazides, and to a somewhat lesser extent the phenylpropionic ones, were better specific inhibitors of bovine serum amine oxidase than the benzoic hydrazides, which were also bound by the enzyme with high affinity, but at a slow rate. Derivatives with p - and m -substituents were more reactive than the o -substituted ones. The chemical nature of the substituent was less important than its position in the phenyl ring and the presence of methylene spacers. These data point to the presence of a hydrophobic site at short distance from the protein carbonyl cofactor, so that simultaneous interaction of the 2 ends of the inhibitor molecule can occur at the 2 sites. The presence of the hydrophobic site was confirmed by the capability of some molecule deprived of the hydrazidic group to act as mild inhibitors. All hydrazides were less reactive by 2–3 orders of magnitude towards pig kidney diamine oxidase and FAD-dependent monoamine oxidase from rat brain mitochondria, while the other compounds showed similar inhibition power against all proteins. The specificity for the bovine enzyme seems therefore to be related to the concerted action of the 2 moieties of the inhibitor molecule.

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).