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FEMS Microbiology Letters, 271 (1), ISSN:0378-1097, ISSN:1574-6968, ISSN:0168-6496, ISSN:0920-8534, ISSN:0168-6445

Historically, natural products have been the most successful source of inspiration for the development of new drugs. Members of the Thymelaeaceae family have been of interest owing to their excellent medicinal value. Given the successful history of natural product-based drug discovery, extracts from the aerial parts of Thymelaea hirsuta were essvaluated for their potential anti-human immunodeficiency virus type 1 (HIV-1) activity. Ethyl acetate extracts from leaves (71B) and branches (72B) of Thymelaea hirsuta showed potent and selective activity against HIV-1 wt (EC50 = 0.8 &micro, g/mL) at non-cytotoxic concentrations (CC50 &gt, 100 &micro, g/mL). They proved to be active against HIV-1 variants carrying clinically relevant NNRTI and NRTI mutations at low concentration (0.3&ndash, 4 &micro, g/mL range) and against the M-tropic strain HIV-1 BaL. The 72B extract, chosen as a lead, was not able to inhibit the RT and protease enzymatic functions. Furthermore, it was not virucidal, since exposure of HIV to high concentration did not affect virus infectivity. The pre-clinical safety profile of this extract showed no adverse effect on the growth of Lactobacilli, and non-toxic concentration of the extract did not influence the Caco-2 epithelial cells monolayer integrity. Additionally, extract 72B prevented syncytia formation at low concentration (0.4 &micro, g/mL). The potent inhibitory effect on the syncytia formation in co-cultures showed that 72B inhibits an early event in the replication cycle of HIV. All of these findings prompt us to carry on new studies on Thymelaea hirsuta extracts.

Enteroviruses are among the most common and important human pathogens for which there are no specific antiviral agents approved by the US Food and Drug Administration so far. Particularly, coxsackievirus infections have a worldwide distribution and can cause many important diseases. We here report the synthesis of new 14 quinoxaline derivatives and the evaluation of their cytotoxicity and antiviral activity against representatives of ssRNA, dsRNA and dsDNA viruses. Promisingly, three compounds showed a very potent and selective antiviral activity against coxsackievirus B5, with EC50 in the sub-micromolar range (0.3 - 0.06 μM). A combination of experimental techniques (i.e. virucidal activity, time of drug addition and adsorption assays) and in silico modeling studies were further performed, aiming to understand the mode of action of the most active, selective and not cytotoxic compound, the ethyl 4-[(2,3-dimethoxyquinoxalin-6-yl)methylthio]benzoate (6).

Linear aromatic N-tricyclic compounds with promising antiviral activity and minimal cytotoxicity were prepared and analyzed in the last years. Specifically, the pyrido[2,3-g]quinoxalinone nucleus was found endowed with high potency against several pathogenic RNA viruses as etiological agents of important veterinary and human pathologies. Following our research program on new antiviral agents we have designed, synthesized and assayed new series of imidazo[4,5-g]quinoline and pyrido[2,3-g]quinoxalinone derivatives. Lead compounds 1-4 were further modified to enhance their antiviral activity and reduce their cytotoxicity. Thus, different substituents were introduced on N atom at position 1 or the O atom at position 2 of the leads; contextually, several groups were inserted on the nitrogen atom at position 7 of diaminoquinoline intermediates. Title compounds were tested in cell-based assays for cytotoxicity and antiviral activity against RNA virus families containing single-stranded (either positive-sense (ssRNA+) or negative-sense (ssRNA-)), and double-stranded genomes (dsRNA), and against two representatives of DNA virus families. Some derivatives emerged as potential leads for further development as antiviral agents against some viruses of public health significance, such as RSV, Reo, BVDV and HCV. Particularly, compounds 4, 11b, 11c, 13c, 15a, 18 and 21 resulted active against BVDV at concentrations ranging from 1.3 to 5 μM. Compound 21 was also evaluated for its activity on the BVDV RdRp. Compound 4 was also tested as potential anti-HCV compound in a subgenomic replication assay. Molecular simulation results provided a molecular rationale for the anti-BVDV activity of these compounds.