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The discovery of antibiotics opened a new era in the treatment against several pathogenic microorganisms that can disable or kill humans. The appearance of the fluoroquinolones (based on nalidixic acid, 4-quinolone-3-carboxylates), in the early 1980's, gave a new impetus in the treatment of infectious diseases. Despite these favourable properties, the earlier fluoroquinolones had limited potency against some clinically important organisms, especially Gram-positive pathogens so that the development of resistance to these organisms has become a serious problem. Thus the development of new fluoroquinolones with a better pharmacokinetic profile, potency, broad spectrum of activity, solubility, prolonged serum half-life and oral and parenteral routes of administration has been a major focus on recent research. The increasing interest in this class led me to review the promising new fluoroquinolones in clinical trials.

Recebido em 20/6/02; aceito em 22/10/02 DRUGS ANTI-HIV: PAST, PRESENT AND FUTURE PERSPECTIVES. Currently available anti-HIV drugs can be classified into three categories: nucleoside analogue reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs). In addition to the reverse transcriptase (RT) and protease reaction, various other events in the HIV replicative cycle can be considered as potential targets for chemotherapeutic intervention: (1) viral adsorption, through binding to the viral envelope glycoprotein gp120; (2) viral entry, through blockage of the viral coreceptors CXCR4 and CCR5; (3) virus-cell fusion, through binding to the viral envelope glycoprotein gp 41; (4) viral assembly and disassembly through NCp7 zinc finger-targeted agents; (5) proviral DNA integration, through integrase inhibitors and (6) INTRODUÇÃOOs vírus estão envolvidos em uma grande variedade de doenças crônicas e degenerativas, sendo responsáveis por mais de 60% das doenças causadas no homem 1 . A luta contra as infecções virais é difícil, pois a replicação viral é um processo intracelular, estando intimamente relacionada ao metabolismo das células infectadas. Um dos vírus mais estudados hoje em dia é o chamado vírus da imunodeficiência humana (VIH) ou "Human Immunodeficiency Ví-rus" (HIV) 2,3 , um vírus da família dos retrovírus (composto de ARN) 4 , capaz de parasitar o sistema imunológico do homem, levando a uma doença infecciosa conhecida como Síndrome da Imunodeficiência Adquirida (SIDA) ou "Acquired Immuno Deficiency Syndrome" (AIDS) 5,6 . O VIH é diferente dos outros vírus porque ataca e danifica o sistema imunológico, que é seu ponto principal de ataque no organismo humano. Um dos componentes do sistema imunológico são os linfócitos T, que atacam diretamente o microorganismo invasor. Dentre os linfócitos T existe uma classe denominada T4 (T CD4+ ou T-auxiliadores), que tem um papel de extrema importância no desencadear da resposta imunitária e na coordenação dessa mesma resposta, sendo o alvo principal do vírus VIH. Este vírus, ao infectar os linfócitos T CD4+, conduz à falta de coordenação do sistema imunológico e à sua progressiva inoperância, acabando por estabelecer uma imunodeficiência 7 . CICLO DA REPLICAÇÃO VIRALPara a obtenção de drogas eficazes no combate ao vírus VIH é extremamente importante conhecer como o vírus infecta o organismo (Figura 1) [8][9][10] . A infecção de uma célula ocorre quando o vírus VIH se liga a um receptor celular, geralmente o T CD4+, por meio de sua proteína gp 120; o vírus então se funde à membrana celular e o conteúdo da cápside é liberado no citoplasma celular. A enzima do VIH, transcriptase reversa, catalisa a produção de uma cópia de ADN a partir do ARN do vírus VIH. A cópia de ADN de dupla hélice é então transportada ao núcleo celular onde uma segunda enzima do VIH, a integrase, catalisa a incorporação do ADN viral ao material genético do hospedeiro. A expressão subseqüente dos genes virais resulta na transcrição d...

In this present review we report different synthetic methodologies for the preparation of fluoroquinolones and their biological properties. The appearance of the fluoroquinolones, a new class of antibacterial agents (based on nalidixic acid, 4-quinolone-3-carboxylates), in early 1980's, gave a new impulse for the international competition to synthesize more effective drugs. Fluoroquinolones have a broad spectrum of activity against Gram-positive, Gram-negative and mycobacterial organisms as well as anaerobes. The fluoroquinolone ciprofloxacin hydrochloride is an important bioterrorist weapon and also an antibiotic used to treat bacterial infection in many different parts of the body, approved for use in patients who have been exposed to the inhaled form of anthrax.

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The cestode E. multilocularis causes the disease alveolar echinococcosis (AE) in humans. The continuously proliferating metacestode (larval stage) of the parasite infects mostly the liver and exhibits tumor-like growth. Current chemotherapeutical treatment options rely on benzimidazoles, which are rarely curative and have to be applied daily and life-long. This can result in considerable hepatotoxicity and thus treatment discontinuation. Therefore, novel drugs against AE are urgently needed. The anti-malarial mefloquine was previously shown to be active against E. multilocularis metacestodes in vitro, and in mice infected by intraperitoneal inoculation of metacestodes when administered at 100 mg/kg by oral gavage twice a week for 12 weeks. In the present study, the same dosage regime was applied in mice infected via oral uptake of eggs representing the natural route of infection. After 12 weeks of treatment, the presence of parasite lesions was assessed in a liver squeeze chamber and by PCR, and a significantly reduced parasite load was found in mefloquine-treated animals. Assessment of mefloquine plasma concentrations by HPLC and modeling using a two-compartment pharmacokinetic model with first-order absorption showed that >90% of the expected steady-state levels (Cmin 1.15 mg/L, Cmax 2.63 mg/L) were reached. These levels are close to concentrations achieved in humans during long-term weekly dosage of 250 mg (dose applied for malaria prophylaxis). In vitro structure-activity relationship analysis of mefloquine and ten derivatives revealed that none of the derivatives exhibited stronger activities than mefloquine. Activity was only observed, when the 2-piperidylmethanol group of mefloquine was replaced by an amino group-containing residue and when the trifluoromethyl residue on position 8 of the quinoline structure was present. This is in line with the anti-malarial activity of mefloquine and it implies that the mode of action in E. multilocularis might be similar to the one against malaria.

Crystal packing patterns for a range of chloroquine derivatives have been investigated. For species where the amine-bound R substituent carries atoms not capable of forming significant hydrogen bonding interactions, i.e. R ¼ methyl (1), n-propyl (2), n-butyl (3), 2-chloroethyl (4), 2-azidoethyl (5), N-H/N hydrogen bonding between the amine and pyridine groups predominate leading to supramolecular chains. In species carrying hydroxyl groups, i.e. R ¼ 2-hydroxylethyl ( 6), 1-butanol (7), and (S)-1-butanol ( 8), the N-H/N interactions are subverted by O-H/N and N-H/O hydrogen bonding that results in the formation of 2-D arrays, establishing an hierarchy of hydrogen bonding interactions in these systems. Despite the differences in hydrogen bonding, globally, the crystal packing in all structures is similar in that the N-H/N mediated supramolecular chains of (1-5) aggregate into layers usually via C-H/p, C-Cl/p and p/p interactions. These layers, as with those formed in (6-8), stack into a 3-D arrangement being consolidated via C-H/Cl and p/p or C-Cl/p interactions.