四氮唑类化合物在抗结核领域的研究进展

四氮唑是羧基的生物电子等排体,不仅可用来取代药物中的羧基以缓解羧基在体内引起的不良反应,还可大大提高药物的脂溶性,进而增加药物的生物利用度.四氮唑类化合物由于具有多种生物活性,近年来在医药领域的应用越发广泛,被科学家认为是最具发展前景的一类化合物.本文将着重介绍近年来四氮唑类化合物在抗结核领域的研究进展,并讨论此类化合物的构-效关系.     

吡唑杂合体的抗疟疾活性

疟疾是由按蚊叮咬或输入携带疟原虫血液引起的一类高传染性疾病,其临床症状包括发热、头痛、呕吐等,如不及时治疗可能危及生命。尽管临床上使用的抗疟疾药物对疟疾的防控不可或缺,但随着长期广泛使用甚至滥用,恶性疟原虫对抗疟药物产生了不同程度的耐药性。为克服耐药性,研发新型抗疟疾药物势在必行。吡唑类化合物具有包括抗疟疾在内的多种生物活性,且某些吡唑类药物已广泛用于临床,故这类化合物引起了药物化学家的持续关注。本文将归纳吡唑杂合体在抗疟疾领域的最新研究进展,并讨论此类化合物的构-效关系。     

吡唑杂合体的抗疟疾活性

疟疾是由按蚊叮咬或输入携带疟原虫血液引起的一类高传染性疾病,其临床症状包括发热、头痛、呕吐等,如不及时治疗可能危及生命。尽管临床上使用的抗疟疾药物对疟疾的防控不可或缺,但随着长期广泛使用甚至滥用,恶性疟原虫对抗疟药物产生了不同程度的耐药性。为克服耐药性,研发新型抗疟疾药物势在必行。吡唑类化合物具有包括抗疟疾在内的多种生物活性,且某些吡唑类药物已广泛用于临床,故这类化合物引起了药物化学家的持续关注。本文将归纳吡唑杂合体在抗疟疾领域的最新研究进展,并讨论此类化合物的构-效关系。     

喹啉——含氮杂环化合物杂合体在抗疟疾领域的研究进展

喹啉类化合物具有毒副作用小和疗效显著等优点,是目前临床上应用最为广泛的抗疟药之一.但是,随着这类药物长期的使用,甚至滥用,耐药疟原虫引起的疟疾业已成为临床医师必须经常面对的棘手问题.因此,亟需研发新的抗疟药.鉴于喹啉和其它含氮杂环化合物具有潜在的抗疟疾活性,将两者通过适当的连接子揉和到一个分子中有可能获得活性更高的抗疟疾候选物,故此类杂合体在抗疟疾领域的应用引起了药物化学家的关注.本文将着重介绍近年来喹啉--含氮杂环化合物杂合体在抗疟疾领域的研究进展,并讨论此类化合物的构-效关系,为寻找疗效更高、毒副作用更小的抗疟疾新药提供理论帮助.     

4-氨基-1,2,4-三唑-5-酮硫代脲酸甲酯的合成及表征

硫脲类化合物由于结构中存在不同取代的肽键(CONH),具有广谱的抗菌性,带有不同取代基团的酰基硫脲可具有抗结核菌、抗病毒、抗疟疾和抗肿瘤等多种生物活性[1-3].三氮唑类等杂环化合物具有很高的生物活性,近年来,一直是科学家研究的热门课题,根据新药研究中的生物等排体和拼合原理,我们设想,把三氮唑环引入到酰基硫脲的结构中,合成了一类新型的酰基硫脲,期望得到生物活性更好的化合物[4-5].     

喹啉杂合体的抗疟疾活性

随着耐药性的广泛传播,耐药疟疾业已成为临床医师所必须经常面对的棘手问题.因此,研发新的抗疟药势在必行.近年来,药物化学家对喹啉类杂合体进行了广泛的研究,发现了若干有苗头的化合物.本文着重探讨近年来喹啉类杂合体在抗疟疾领域的研究进展,为研发对敏感型和耐药型疟疾均有效的新型抗疟药提供理论支持.     

苯基恶唑烷酮类化合物合成研究(英文)

恶唑烷酮类化合物是一类新的抗革兰阳性菌化合物。作为恶唑烷酮类化合物的前体药物,苯基取代的恶唑烷酮类可以提高此类化合物的溶解度。本文对苯基恶唑烷酮类的合成关键步骤改进研究,Suzuki偶联反应替代了文献报道的Stille反应,避免了对环境有害的锡化合物的使用。     

三嗪类化合物在抗疟疾领域的研究进展

三嗪类化合物具有稳定性好、易形成多种非共价键作用等优点,而且其中的某些含有三嗪结构单元的药物已在临床上广泛使用,故这类化合物引起了药物化学家的极大兴趣.本文着重归纳了近年来三嗪尤其是1,3,5-三嗪类化合物在抗疟疾领域的研究进展,并探讨了这类化合物的构-效关系,为寻找三嗪类抗疟疾新药提供理论依据.     

β-内酰胺类化合物在抗疟疾领域的研究进展

β-内酰胺类化合物不仅是临床上使用最为广泛的广谱抗生素,还具有抗结核、抗肿瘤、抗炎、抗氧化、抗病毒和抗疟疾等多种生物活性.其中,β-内酰胺类化合物在抗疟疾领域的应用引起了药物化学家的持续关注.本文将着重介绍近年来β-内酰胺类化合物在抗疟疾领域的研究进展,并讨论此类化合物的构-效关系,为寻找疗效更高、毒副作用更小的β-内酰胺类抗疟疾新药提供理论依据.     

过氧化物-喹啉杂合体的抗疟疾活性

以青蒿素(ART)为主的联合疗法(ACT)是目前治疗疟疾最有效的途径,是WHO推荐的抗疟疾标准疗法.然而,ART存在生物利用度低、复发率高、溶解性差、价格昂贵等缺点,且耐ART疟原虫已然出现,故研发新的抗疟药势在必行.喹啉类药物具有优秀的抗疟疾活性,是目前临床上应用最为广泛的抗疟药.研究显示,内过氧化物单元是ART及其衍生物具有抗疟疾活性所必需的药效团,故将过氧化物与喹啉杂合或许可得到活性更高的抗疟疾候选物.药物化学家有针对性的设计合成并筛选了众多过氧化物-喹啉杂合体的体外抗疟原虫和体内抗疟疾活性,并得到了若干有苗头的候选物.本文将介绍近年来过氧化物-喹啉杂合体在抗疟疾领域的研究进展,并讨论此类化合物的构-效关系,以期为更合理的设计抗疟新药提供支持.     

Recent patent reviews on small molecule-based antimalarial drugs

Malaria is the number one disease in the world responsible for 1-3 million deaths each year. The world wide number of malaria patients is estimated at 400 to 900 million. Approximately one third of the world's population lives in malaria-endemic areas, including Central and South America, Asia, and Africa. Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale and Plasmodium malariae are malaria parasites responsible for infecting humans. Mosquitoes that carry malaria parasites have become resistant to insecticides, and the deadliest parasites have become resistant to previously effective antimalarial drugs such as chloroquine, quinine and other clinically used agents. Because of the widespread incidence of malaria in certain parts of the world and because of the increasing parasite resistance to standard anti-malarial agents, there is an urgent need for introducing new effective drugs. This review presents the recent patents that reveal development of novel antimalarial drugs.     

New trends in anti-malarial agents

Malaria is the major parasitic infection in many tropical and subtropical regions, leading to more than one million deaths (principally young African children) out of 400 million cases each year (WHO world health report 2000). More than half of the world's population live in areas where they remain at risk of malaria infection. During last years, the situation has worsened in many ways, mainly due to malarial parasites becoming increasingly resistant to several antimalarial drugs. Furthermore, the control of malaria is becoming more complicated by the parallel spread of resistance of the mosquito vector to currently available insecticides. Discovering new drugs in this field is therefore a health priority. Several new molecules are under investigation. This review describes the classical treatments of malaria and the latest discoveries in antimalarial agents, especially artemisinin and its recent derivatives as well as the novel peroxidic compounds.     

Novel rational drug design strategies with potential to revolutionize malaria chemotherapy

Efforts to develop an effective malaria vaccine are yet to be successful and thus chemotherapy remains the mainstay of malaria control strategy. Plasmodium falciparum, the parasite that causes about 90% of all global malaria cases is increasingly becoming resistant to most antimalarial drugs in clinical use. This dire situation is aggravated by reports from Southeast Asia, of the parasite becoming resistant to the "magic bullet" artemisinins, the last line of defense in malaria chemotherapy. Drug development is a laborious and time consuming process, and thus antimalarial drug discovery approaches currently being deployed largely include optimization of therapy with available drugs--including combination therapy and developing analogues of the existing drugs. However, the latter strategy may be hampered by crossresistance, since agents that are closely related chemically may share similar mechanisms of action and/or targets. This may render new drugs ineffective even before they are brought to clinical use. Evaluation of drug-resistance reversers (chemosensitizers) against quinoline-based drugs such as chloroquine and mefloquine is another approach that is being explored. Recently, evaluation of new chemotherapeutic targets is gaining new impetus as knowledge of malaria parasite biology expands. Also, single but hybrid molecules with dual functionality and/or targets have been developed through rational drug design approach, termed as "covalent bitherapy". Since desperate times call for radical measures, this review aims to explore novel rational drug-design strategies potentially capable of revolutionizing malaria therapy. We thus explore malaria apoptosis machinery as a novel drug target, and also discuss the potential of hybrid molecules as well as prodrugs and double prodrugs in malaria chemotherapy.     

Pharmacodynamics of antimalarial chemotherapy

Malaria chemotherapy is under constant threat from the emergence and spread of multidrug resistance of Plasmodium falciparum. Resistance has been observed to almost all currently used antimalarials. Some drugs are also limited by toxicity. A fundamental component of the strategy for malaria chemotherapy is based on prompt, effective and safe antimalarial drugs. To counter the threat of resistance of P. falciparum to existing monotherapeutic regimens, current malaria treatment is based principally on the artemisinin group of compounds, either as monotherapy or artemisinin-based combination therapies for treatment of both uncomplicated and severe falciparum malaria. Key advantages of artemisinins over the conventional antimalarials include their rapid and potent action, with good tolerability profiles. Their action also covers transmissible gametocytes, resulting in decreased disease transmission. Up to now there has been no prominent report of drug resistance to this group of compounds. Treatment of malaria in pregnant women requires special attention in light of limited treatment options caused by potential teratogenicity coupled with a paucity of safety data for the mother and fetus. Treatment of other malaria species is less problematic and chloroquine is still the drug of choice, although resistance of P. vivax to chloroquine has been reported. Multiple approaches to the identification of new antimalarial targets and promising antimalarial drugs are being pursued in order to cope with drug resistance.     

Pharmacodynamics of antimalarial chemotherapy

Malaria chemotherapy is under constant threat from the emergence and spread of multidrug resistance of Plasmodium falciparum. Resistance has been observed to almost all currently used antimalarials. Some drugs are also limited by toxicity. A fundamental component of the strategy for malaria chemotherapy is based on prompt, effective and safe antimalarial drugs. To counter the threat of resistance of P. falciparum to existing monotherapeutic regimens, current malaria treatment is based principally on the artemisinin group of compounds, either as monotherapy or artemisinin-based combination therapies for treatment of both uncomplicated and severe falciparum malaria. Key advantages of artemisinins over the conventional antimalarials include their rapid and potent action, with good tolerability profiles. Their action also covers transmissible gametocytes, resulting in decreased disease transmission. Up to now there has been no prominent report of drug resistance to this group of compounds. Treatment of malaria in pregnant women requires special attention in light of limited treatment options caused by potential teratogenicity coupled with a paucity of safety data for the mother and fetus. Treatment of other malaria species is less problematic and chloroquine is still the drug of choice, although resistance of P. vivax to chloroquine has been reported. Multiple approaches to the identification of new antimalarial targets and promising antimalarial drugs are being pursued in order to cope with drug resistance.     

Plasmodium falciparum: Multidrug resistance

Malaria is the most lethal and debilitating disease caused by the protozoan parasite Plasmodium worldwide. The most severe forms of disease and the incidence rates of mortality are associated with P. falciparum infections. With the identification of disease source and symptoms, many chemical entities were developed naturally and synthetically for administration as a potential antimalarial drug. The major classes of approved antimalarial drugs that are governed as first‐line treatment in tropical and subtropical areas include quinolines, naphthoquinones, antifolates, 8‐aminoquinolines, and endoperoxides. However, the efficacy of antimalarial drugs has decreased due to ongoing multidrug resistance problem to current drugs. With increasing resistance to the current antimalarial artemisinin and its combination therapies, malaria prophylaxis has declined gradually. New‐generation antimalarial and novel drug target are required to check the incidence of malaria resistance. This review summarizes the emergence of multidrug resistance to known antimalarial and the development of new antimalarial to resolve drug resistance condition. Few essential proteins are also discussed that can be considered as novel drug target against malaria in future.     

Novel drug targets in malaria parasite with potential to yield antimalarial drugs with long useful therapeutic lives

The status of chemotherapy as the main strategy in malaria control is rapidly being eroded by development of drug resistant Plasmodia, causing malaria to be dubbed a "re-emerging disease". To counter this misfortune, there is an urgent need to develop novel antimalarial drugs capable of delaying resistance, or circumventing it altogether. Mode of action of antimalarial drugs, inter alia, has a bearing on their useful therapeutic lives (UTLs), with single target drugs having short UTLs compared with drugs which possess pleiotropic action. Quinolines and artemisinins are the two classes of drugs with pleiotropic action and subsequently long UTLs. All other antimalarials are single-target drugs, and have been rendered ineffective within 1 to 5 years of their introduction for clinical use. This strongly underlines the need for development of new antimalarial therapies possessing long UTLs. The present review explores novel drug targets within the malaria parasite that may be exploited in the search for novel drugs that possess long and UTLs.     

Metallocenes and malaria: a new therapeutic approach

Rapid development of significant resistance to antimalarial drugs has been a major force driving research to identify and develop new compounds. The use of synthetic organometallic complexes seems to be promising for treatment of malaria infections. Recent progress in identification and development of new drugs promises to lead to a much greater range of antimalarial agents. Organometallic complexes and metalloporphyrins have shown in vitro activity against Plasmodium falciparum. Ferroquine (ferrocenyl chloroquine) is more active than chloroquine against strains and isolates of P. falciparum and shows efficacy against murine parasites.