205 research outputs found
Benzimidazole-2-Phenyl-Carboxamides as Dual-Target Inhibitors of BVDV Entry and Replication
Bovine viral diarrhea virus (BVDV), also known as Pestivirus A, causes severe infection mostly in cattle, but also in pigs, sheep and goats, causing huge economical losses on agricultural farms every year. The infections are actually controlled by isolation of persistently infected animals and vaccination, but no antivirals are currently available to control the spread of BVDV on farms. BVDV binds the host cell using envelope protein E2, which has only recently been targeted in the research of a potent and efficient antiviral. In contrast, RdRp has been successfully inhibited by several classes of compounds in the last few decades. As a part of an enduring antiviral research agenda, we designed a new series of derivatives that emerged from an isosteric substitution of the main scaffold in previously reported anti-BVDV compounds. Here, the new compounds were characterized and tested, where several turned out to be potent and selectively active against BVDV. The mechanism of action was thoroughly studied using a time-of-drug-addition assay and the results were validated using docking simulations
In vitro antitumorsko i antivirusno djelovanje novih benzotiazola i 1,3,4-oksadiazol-2-tion derivata
A series of new benzothiazole derivatives 6a-h have been synthesized, in five steps, from substituted phenols via the 1,3,4-oxadiazole-2-thiones 5a-h. The in vitro antitumor activity of the compounds obtained was investigated and the benzothiazol derivatives 6d and 6e showed high effects on leukaemia cell lines CCRF-CEM (CC50 = 12 ± 2 ”mol L1, 8 ± 1 ”mol L1, respectively). These compounds are leading candidates for further development. The title compounds were tested against representatives of several virus families containing single stranded RNA genomes, either positive-sense (ssRNA+), or negative-sense (RNA-), and against double-stranded RNA genomes (dsRNA), as well as some Flaviviridae viruses.U pet reakcijskih koraka sintetizirana je serija novih derivata benzotiazola 6a-h polazeÄi iz supstituiranih fenola preko 1,3,4-oksadiazol-2-tiona 5a-h. Sintetizirani spojevi ispitani su na antitumorsko djelovanje. Benzotiazol derivati 6d i 6e pokazali su jak uÄinak na staniÄnu liniju leukemije CCRF-CEM (CC50 = 12 ± 2, odnosno 8 ± 1 ”mol L1). Ti su spojevi predvodni spojevi za daljnji razvoj. Nadalje, novi su spojevi testirani na djelovanje na nekoliko tipova virusa koji sadrĆŸe bilo pozitivni (ssRNA+) bilo negativni (RNA-) jednolanÄani RNA genom ili dvolanÄani RNA genom (dsRNA), te na neke Flaviviridae viruse
N,N'(4,5-Dihydro-1H-imidazol-2-yl)3-aza-1,10-decane-diamidine and N,N'(4,5-dihydro-1H-imidazol-2-yl)3-aza-1,12-dodecane-diamidine antagonize cell proliferation as selective ligands towards topoisomerase II
Sintesi e valutazione biologica di nuovi "lead compounds" per la terapia antitubercolare. Derivati del 2-(benzotriazol-1(2)-il)-3- acrilonitrile e delle chinossaline 1,4-diossido
L'insorgenza sempre piĂč elevata di ceppi di M. tuberculosis chemioresistenti ai farmaci abitualmente
impiegati in terapia (MDR) ha spronato la ricerca di nuovi "lead compounds" per lo sviluppo di molecole
che, agendo con meccanismo diverso da quello dei farmaci attualmente impiegati in terapia, possano
contribuire a superare il problema della farmacoresistenza. In quest'ambito le nostre ricerche si sono orientate
verso due differenti direzioni. La prima prende lo spunto dai risultati ottenuti in passato da vari gruppi di
ricerca con alcuni derivati di sintesi di sistemi eterociclici aromatici quali benzimidazolo, benzotiazolo,
benzoisotiazolo e benzofurano, che avevano dimostrato attivitĂ Â antimicobatterica in vitro soprattutto
nei confronti di ceppi MDR.
La seconda linea di ricerca si Ăš basata sulla nota attivitĂ Â antibatterica e soprattutto antimicotica
della chinossalina 1,4-diossido, con la consapevolezza che spesso l'attivitĂ Â antimicobatterica Ăš
associata a quella antifungina
Imidazolo [1,2-a] e 1,2,4-triazolo[4,3-a] chinossaline analoghe degli antifolici metotrexato e trimetrexato
Abbiamo progettato una nuova serie di chinossaline, nelle quali lâanello pirrolico Ăš stato sostituito con unâanello imidazolico
o con uno triazolico lasciando nelle posizioni 2, 5, 6, 7 e 8 dellâanello chinossalinico gli stessi
sostituenti precedentemente esaminati.
Di questi composti verranno descritti la sintesi e i risultati farmacologici relativi alla loro attivitĂ
Synthesis and Biological Evaluation of New 3-Phenyl-1-[(4-arylpiperazin-1-yl)alkyl]-piperidine-2,6-diones
A set of 13 alkyl derivatives of 3-phenylpiperidine-2,6-dione were synthesized. Newly obtained compounds were investigated in vitro against HIV-1 and other selected viruses. The benzyl 3f and fluorophenyl 3g derivatives showed moderate protection against CVB-2 and the compound 3g also against HSV-1. Derivatives were tested also for their antibacterial and antifungal activity. The molecular structures of 3a and 3d were determined by an X-ray analysis
Structure-activity relationship studies on new DABOS: effect of substitutions at pyrimidine C-5 and C-6 positions on anti-HIV-1 activity.
Several 5-alkyl, 5-alkenyl, 5-iso-alkyl, 5-halo, 5-aminomethyl and 5-carboxy derivatives of S-DABOs (dihydro-alkyl (or cyclo-alkyl)thio-benzyloxopyrimidines), DATNOs (dihydro-alkylthionaphthylmethyl-oxopyrimidines) and F2-S-DABOs (dihydro-alkyl (or cyclo-alkyl)thio-2,6-difluorobenzyl-oxopyrimidines) have been prepared and tested as anti-HIV-1 agents. S-DABO derivatives bearing at C-6 position monosubstituted phenylmethyl or heteroarylmethyl units have also been synthesized. 2-Alkylthio-3,4-dihydropyrimidin-4(3 H)-one derivatives of F2- S-DABO series bearing small alkyl groups at C-5 proved to be potent inhibitors of HIV-1 replication in vitro with selectivity indexes ranging from 250 to <2500
Antitumor Agents. 2. Synthesis, Structure-Activity Relationships, and Biological Evaluation of Substituted 5H-Pyridophenoxazin-5-ones with Potent Antiproliferative Activity
New antiproliferative compounds, 5H-pyrido[3,2-a]phenoxazin-5-ones (1-10), 5H-benzophenoxazin- 5-one (11), 5H-pyrido[2,3-a]phenoxazin-5-one (12), 5H-pyrido[3,4-a]phenoxazin-5-one
(13), and 5H-pyrido[4,3-a]phenoxazin-5-one (14), were synthesized and evaluated against representative human neoplastic cell lines. The excellent cytotoxic activity of these polycyclic
phenoxazinones, structurally related to the actinomycin chromophore, is discussed in terms of structural changes made to rings A and D (Chart 1). Electron-withdrawing or electron-donating
substituents were introduced at different positions of ring A to probe the electronic and positional effects of the substitution. A nitro group in R2 or in R1 increases the cytotoxic activity,
whereas electron-donating methyl groups in any position lead to 10- to 100-fold decreasing of the activity. The low antiproliferative activity of benzophenoxazinone 11 and pyridophenoxazinones
13 and 14 confirms the crucial role of pyridine nitrogen in the W position of ring D in DNA binding. The unexpected high activity exhibited by 12, which has the nitrogen in the
X position, could be ascribed to a different mechanism of action, which needs further investigation
Dichloro-Phenyl-Benzotriazoles: A New Selective Class of Human Respiratory Syncytial Virus Entry Inhibitors
Human Respiratory Syncytial Virus (RSV) is the primary cause of bronchopneumonia in infants and children worldwide. Clinical studies have shown that early treatments of RSV patients with ribavirin improve prognosis, even if the use of this drug is limited due to myelosuppression and toxicity effects. Furthermore, effective vaccines to prevent RSV infection are currently unavailable. Thus, the development of highly effective and specific antiviral drugs for pre-exposure prophylaxis and/or treatment of RSV infections is a compelling need.
In the quest of new RSV inhibitors, in this work we evaluated the antiviral activity of a series of variously substituted 5,6-dichloro-1-phenyl-1(2)H-benzo[d][1,2,3]triazole derivatives in cell-based assays. Several 1- and 2-phenyl-benzotriazoles resulted fairly potent (\ub5M concentrations) inhibitors of RSV infection in plaque reduction assays, accompanied by low cytotoxicity in human highly dividing T lymphoid-derived cells and primary cell lines. Contextually, no inhibitory effects were observed against other RNA or DNA viruses assayed, suggesting specific activity against RSV. Further results revealed that the lead compound 10d was active during the early phase of the RSV infection cycle. To understand whether 10d interfered with virus attachment to target cells or virus-cell fusion events, inhibitory activity tests against the RSV mutant strain B1 cp-52 \u2013 expressing only the F envelope glycoprotein \u2013 and a plasmid-based reporter assay that quantifies the bioactivity of viral entry were also performed. The overall biological results, in conjunction with in silico modeling studies, supported the conclusion that the RSV fusion process could be the target of this new series of compounds
Synthesis, cytotoxicity and antiviral evaluation of new series of imidazo[4,5-g]quinoline and pyrido[2,3-g]quinoxalinone derivatives
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\ua0\u3bcM. 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
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