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A novel family of non-nucleoside reverse transcriptase inhibitors (NNRTIs) active at submicromolar concentrations was discovered. The new derivatives are 1-[2-(diarylmethoxy)ethyl]imidazoles bearing substituents both at benzene and imidazole rings. The most potent derivatives were those having nitro and methyl groups as substituents in the imidazole ring. Among 10 test derivatives compound 6dwas found to be as potent as nevirapine and was selected as a lead for further studies.

A series of indolo[3,2-c]cinnoline derivatives was prepared and tested to evaluate their biological activity. Most of them inhibited the proliferation of leukemia, lymphoma and solid tumor-derived cell lines at micromolar concentrations, whereas none of the compounds were active against HIV-1. With the exception of 7gScheme 1(a) RR1R2H; (b) RR2H, R1Cl; (c) RR1H, R2Cl; (d) RR1H, R2Me; (e) ROMe, R1R2H (f) RCl, R1R2H; (g) RBr, R1R2H; (h) RNO2, R1R2H; (i) RNO2, R1Cl, R2H.Table 1Antiproliferative activity of indolo[3,2-c]cinnolinesIC50[μM]aCell lines7a7b7c7d7e7f7g7h7iDoxoLeukemia/lymphomaL1210121.03.5305024>1000.3ND0.23Wil2-NS4.50.51.0201018890.21.10.02CCRF-SB50.72.8213.227>1000.21.10.01Raji6.80.817>1012>10>1001.21.80.08CCRF-CEM50.51.9107.35.0540.082.20.10MOLT-43.30.41.6123.212>1000.080.20.03MT-42.20.94.7252.350>1000.30.50.09CarcinomaHT-29505.20.82.8>502.1941.94.50.05HeLa8.91.01048.133>10>1007.71.00.25ACHN>5.03.11.241.515.5>10>1003.03.00.4456374.00.32.11019>1018.90.72.70.02NeuroblastomaIMR-325.80.6NDND7.0NDNDNDND<0.01aCompound concentration required to reduce cell multiplication by 50% under conditions allowing untreated controls to undergo at least three consecutive rounds of multiplication. L1210, mouse leukemia; Wil2-NS, human splenic B-lymphoblastoid cells; CCRF-SB, human acute B-lymphoblastoic leukemia; Raij, human Burkitt lymphoma; CCRF-CEM and MOLT-4, human acute T-lymphobastic leukemia; MT-4, human CD4+T-cells containing an integrated HTLV-1 genome; HT-29, human colon adenocarcinoma; HeLa, human cervix carcinoma; ACHN, human renal adenocarcinoma; 5637, human bladder carcinoma; IMR-32, human neuroblastoma. ND: not determined.Table 3Antifungal activity of indolo[3,2-c]cinnolinesMIC [μM]aSpecies7a7b7c7d7e7f7g7h7iMiconazoleC. albicans1509.412>200>200>200>2001.6667.5C. parapsilosis1.82.3100>200>200>200>2001.6220.9C. paratropicalis371950>200>200>200>2001.6667.5C. neoformans0.80.16.2>200>200>200>2001.67.40.9T. mentagrophytes1.875NDND>200NDNDNDND0.9A. fumigatus5.04.7200>200>200>200>2003.12001.9aMinimum inhibitory concentration. ND: not determined.Table 4Antibacterial activity indolo[3,2c]cinnolinesMIC [μM]aSpecies7a7b7c7d7e7f7g7h7iStreptomycinStreptococcus0.20.10.46.23.16.2>2000.050.32.1Staphlyococcus0.10.070.46.26.26.21000.020.094.2Salmonella>200>200>200>200>200>200>2003.12008.6Shigella>200>200>200>200>200>200>2001.6662.1aMinimum inhibitory concentration., all title compounds showed antibacterial activity against gram-positive bacteria, being up to 200 times more potent than the reference drug streptomycin. Some of the indolo[3,2-c]cinnolines were also endowed with good antifungal activity, particularly against Cryptococcus neoformans.

The syntheses of 4-amino-1-(β-D-ribofuranosyl)-1H-1,2,3-triazolo[4,5-c]pyridine (8-aza-3-deazaadenosine, 1), 4-amino-1-(2-deoxy-β-D-erythro-pentofuranosyl)-1H-1,2,3-triazolo[4,5-c]pyridine (2′-deoxy-8-aza-3-deazaadenosine, 2), and their N8and N7glycosylated analogues (12,13, 21,22) and 4-amino-1-(2,3-dideoxy-β-D-erythro-pentof uranosyl)-1H-1,2,3-triazolo [4,5-c]pyridine (2′,3′-dideoxy-8-aza-3-deazaadenosine, 3) were carried out by glycosylation of the 4-chloro-3H-1,2,3-triazolo[4,5-c]pyridine anion. The anomeric configuration as well as the position of glycosylation were determined by 1H-, 13C-NMR, UV and N.O.E. difference spectroscopy. Nucleoside (2) and its parent compound 2′-deoxy-3-deazaadenosine were found active against ASFV and VSV. The 4-chloro-2-(β-D-ribofuranosyl)-2H-1,2,3-triazolo[4,5-c] pyridine (9) was active against Coxsackie B1, whereas none of the 8-aza-3-deaza purine nucleosides, compound (3) included, was active against HIV-1. The 6-chloro derivatives of 8-aza-3-deazapurine ribo- and 2′-deoxyribonucleosides (11) and (20) showed some activity against LoVo human colon adenocarcinoma.

2',3'-Dideoxy-8-aza-1-deazaadenosine (21) and its α-anomer (20) were synthesized via glycosylation of 7-chloro-3H-1,2,3-triazolo[4,5-b]pyridi-ne with 2,3-dideoxy-5-O-[(1, 1)-dimethylethyl)diphenylsilyl]-D-glycero-o-pen-tofuranosyl chloride. The reaction gave a mixture of α- and β-anomers of N3-, N4- and N1-glycosylated regioisorners (12-15). The α- and β-anomers of the N4-glycosylated isomer 26 and 27 were also synthesized through the glycosylation of 8-aza-1-deazaadenine with 1-acetoxy-2,3-dideoxy-5-O-f(1,1-di-methylethyl)dimethylsilyl]-D-glycero-pentouranose. These dideoxynucleo-sides and a series of previously synthesized 8-aza-1-deazapurine nucleosidcs were tested for activity against several DNA and RNA viruses, HIV-1 included. The α- and β-anomers of 7-chloro-3-(2-deoxy-D-erythro-pentofuranosyl)-3H-1,2,3-triazolo[4,5-b]pyridine (3a and 4) showed activities against Sb-1 and Coxs viruses. The α- and β-anomers of 2',3'-dideoxy-8-aza-1-deazaadenosine (20 and 21) were found active as inhibitors of adenosine deaminase.

A comparative study on the "in vitro" activity of various nucleoside analogues has been carried out on the Lisbona 60 strain of ASFV adapted to VERO cells. β-D-xylofuranosyl-adenine and β-D-lyxofuranosyl-guanine emerged as the compounds endowed with the most favourable selectivity index.

A high yielding synthesis of 4-O-acylated pyrlmldines is presented. These products are selective reagents for amine acylatlon. The antitumor and antimicrobial activity of compounds 1and 2cis also reported.

The current model of poliovirus morphogenesis postulates a fundamental role for procapsid, 80S shells that, upon interaction with viral RNA and subsequent proteolytic cleavage, give rise to complete virus particles. Although 80S sedimenting particles can, indeed, be isolated from cytoplasmic extracts of infected cells, their physical properties differ from those reported for procapsids. Far from being stable structures, they can be dissociated by pH 8.5 and 0.1% sodium dodecyl sulfate into slower-sedimenting subunits. The reasons for this discrepancy were investigated, and two main modalities leading to the appearance of procapsids in vitro were identified. The first involves a temperature-mediated conversion of dissociable 80S particles into stable 80S procapsids, and the second involves the self-assembly of endogenous 14S subunits, also primed by an increase in the temperature of cytoplasmic extracts.

The syntheses and antiviral activity of analogues of the anti-HIV agents PMEA, PMEDAP, (R)-PMPA, (R)-PMPDAP are described. In these analogues the adenine moiety is replaced by 4,6-diamino-5-nitro-pyrimidine (the aglycon of clitocine) or 2,4,6-triamino-5-nitro-pyrimidine. The synthesis of similar acyclic phosphonates related to PMEG and (R)-2'-methyl-PMEG is also reported. Some compounds proved to be active as anti-HIV agents.

A previously undetected subviral particle, designated the 55S particle because of its position in sucrose density gradients, has been found in cytoplasmic extracts of poliovirus-infected cells. It contains no RNA, is composed of equimolar amounts of the structural polypeptides P1AB, P1C, and P1D, and is stable in vitro under a variety of conditions: presence or absence of EDTA, dilution in low- or high-ionic-strength buffers, suspension in buffers up to pH 10, incubation at 37 degrees C, and centrifugation to equilibrium in CsCl gradients (where it bands at a density of 1.285 g/cm3). Conventional pulse-chase experiments show that 55S particles are the products of the assembly of 14S subunits and the precursors of virions. These data led to the formulation of a model of poliovirus morphogenesis in which the conversion of capsomers into 73S empty capsids does not occur directly, but through the formation of an intermediate structure, the 55S particle.

- The 4-amino-1-(2.3-dideoxy-β-D-glycero-pent-2-enofurano-syl)-1H-irnidazo[4,5-c]pyridine (1) and 4-amino-1-(2,3-dideoxy-β-D-gfycero-pentofuranosyl)-1H-imidazo[4,5-c]pyridine (2), 3-deaza analogues of the anti-HIV agents 2'.3'-didehydro-2',3'-dideoxyadenosine (d4A) and 2',3'-dideoxy-adenosine (ddA), have been synthesized. The reaction of 3-deazaadenosine (3) with 2-acetoxyisobutyryl bromide yielded a mixture of cis and trans 2',3'-ha-lo acetates which was convertcd into olefinic nucleoside (1) on treatment with a Zn/Cu couplc and then with methanolic ammonia. The 2',3'-dideoxy-3-deazaadenosine (2) was obtained by catalytic reduction of 1. A number of phosphate triester derivatives of 2 have also been prepared. The diethyl-, dipropyl- and dibutylpliospliates 7a-c and 3-deazaadenosine have shown anti-HIV activity at non-cytotoxic doses. Compounds 7a-c have also shown significant cytostatic activity against murine colon adenocarcinoma cells.

8-Aza-analogues of the potent antiviral nucleotide analogues 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) and 9-[2-(phosphonomethoxy)-ethyl]guanine (PMEG) were prepared and evaluated for activity against human immunodeficiency viruses. When compared to the parent compounds, 8-aza-PMEA (1) and -PMEG (2) were less cytotoxic for MT-4 cells, but also less potent against HIV-1 and HIV-2. A new synthesis of PMEG starting from guanine is also reported.

A new, more facile synthesis of oxazofurin, a structural analogue of tiazofurin, selenazofurin and ribavirin, has been carried out by rhodium catalyzed reaction of ethyl α-formyl-diazoacetate with 2,3, 5-tri-O-benzoyl-β-D-ribofu-ranosyl cyanide. When evaluated against DNA and RNA viruses, HIV-1 inclu-ded, oxazofurin was found inactive. It was also ineffective in potentiating the anti-HIV activity of 2', 3'-dideoxyadenosine.

The impact of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19, is global and unprecedented. Although remdesivir has recently been approved by the FDA to treat SARS-CoV-2 infection, no oral antiviral is available for outpatient treatment.