naphthoquinones and Tuberculosis

Mycobacterium tuberculosis (Mtb) causes one of the most grievous pandemic infectious diseases, tuberculosis (TB), with long-term morbidity and high mortality. The emergence of drug-resistant Mtb strains, and the co-infection with human immunodeficiency virus, challenges the current WHO-TB stewardship programs. The first-line anti-TB drugs, isoniazid (INH) and rifampicin (RIF), have become extensively obsolete in TB control from chromosomal mutations during the last decades. However, based on clinical trial statistics, the production of well-tolerated anti-TB drug(s) is miserably low. Alternately, semi-synthesis or structural modifications of first-line obsolete antitubercular drugs remain as the versatile approach for getting some potential medicines. The use of any suitable phytochemicals with INH in a hybrid formulation could be an ideal approach for the development of potent anti-TB drug(s). The primary objective of this review was to highlight and analyze available INH-phytochemical hybrid research works. The utilization of phytochemicals through chemical conjugation is a new trend toward the development of safer/non-toxic anti-TB drugs.

Topics: Antitubercular Agents; Benzaldehydes; Drug Development; Glycosides; Humans; Indoles; Isoniazid; Molecular Structure; Mycobacterium tuberculosis; Naphthoquinones; Phytochemicals; Steroids; Structure-Activity Relationship; Terpenes; Tuberculosis; Tuberculosis, Multidrug-Resistant

Naphthoquinoidal compounds are of great interest in medicinal chemistry. In recent years, several synthetic routes have been developed to obtain bioactive molecules derived from lapachones. In this mini-review, we focus on the synthetic aspects and strategies used to design these compounds and on the biological activities of these substances for the development of drugs against the neglected diseases leishmaniasis and Chagas disease as well as malaria, tuberculosis and cancer. Three strategies used to develop bioactive naphthoquinoidal compounds are discussed: (i) C-ring modification, (ii) redox centre modification and (iii) A-ring modification. Among these strategies, reactions such as copper-catalysed azide-alkyne cycloaddition (click chemistry), palladium-catalysed cross couplings, and heterocyclisations will be discussed for the development of naphthoquinoidal compounds against Trypanosoma cruzi, Leishmania and cancer. The aim of derivatisation is the generation of novel molecules that inhibit cellular organelles/processes, generate reactive oxygen species (ROS) and increase lipophilicity to enhance penetration through the plasma membrane. Modified lapachones have emerged as promising prototypes for the development of drugs against neglected diseases and cancer.

Topics: Animals; Cell Membrane; Chagas Disease; Humans; Hydrophobic and Hydrophilic Interactions; Leishmania; Leishmaniasis; Malaria; Naphthoquinones; Neoplasms; Reactive Oxygen Species; Trypanosoma cruzi; Tuberculosis

Tuberculosis (TB) is the cause of more than one million deaths worldwide, and despite being a curable disease, some factors can make therapy difficult, emphasizing the need for the development of new drugs that may potentiate the action of the classic anti-TB antimicrobials. Naphthoimidazoles show a broad spectrum of biological activities, including antimycobacterial activity. The aim of this study was to evaluate the anti-Mycobacterium tuberculosis activity of nine naphthoimidazoles, alone and combined with isoniazid (INH) and rifampicin (RIF). We evaluated the minimum inhibitory concentration (MIC) of the compounds, the fractional inhibitory concentration of the combinations of the naphthoimidazoles with INH or RIF, and the cytotoxicity of these compounds. Eight compounds showed MICs ranging from 1.56 to 25 μg/mL and the presence of substituents on phenyl groups shown to be essential for antimycobacterial activity. Four compounds showed additivity with both INH and RIF and showed SI values higher than 10, indicating safety. Thus, considering the antimycobacterial activity and the absence of antagonism between naphthoimidazoles and the two main drugs for TB treatment, these compounds could be scaffolds for the development of new anti-TB drugs.

Topics: Antitubercular Agents; Drug Discovery; Drug Resistance, Bacterial; Drug Therapy, Combination; Humans; Imidazoles; Isoniazid; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Naphthoquinones; Rifampin; Structure-Activity Relationship; Tuberculosis

Tuberculosis and other bacterial diseases represent a significant threat to human health. The DNA topoisomerases are excellent targets for chemotherapy, and DNA gyrase in particular is a well-validated target for antibacterial agents. Naphthoquinones (e.g. diospyrin and 7-methyljuglone) have been shown to have therapeutic potential, particularly against Mycobacterium tuberculosis. We have found that these compounds are inhibitors of the supercoiling reaction catalyzed by M. tuberculosis gyrase and other gyrases. Our evidence strongly suggests that the compounds bind to the N-terminal domain of GyrB, which contains the ATPase active site, but are not competitive inhibitors of the ATPase reaction. We propose that naphthoquinones bind to GyrB at a novel site close to the ATPase site. This novel mode of action could be exploited to develop new antibacterial agents.

Topics: Adenosine Triphosphate; Anti-Infective Agents; Binding Sites; Catalytic Domain; DNA; DNA Gyrase; Escherichia coli; Humans; Inhibitory Concentration 50; Mass Spectrometry; Models, Chemical; Mycobacterium tuberculosis; Naphthoquinones; Protein Binding; Protein Structure, Tertiary; Staphylococcus aureus; Surface Plasmon Resonance; Tuberculosis

Topics: Acquired Immunodeficiency Syndrome; AIDS-Related Opportunistic Infections; Amphotericin B; Antifungal Agents; Antiprotozoal Agents; Antiviral Agents; Atovaquone; Candidiasis, Oral; Clindamycin; Clotrimazole; Cryptosporidiosis; Cytomegalovirus Infections; Dapsone; Didanosine; Drug Combinations; Drug Therapy, Combination; Fluconazole; Flucytosine; Folic Acid Antagonists; Foscarnet; Glucuronates; Herpes Simplex; Herpes Zoster; Humans; Isoniazid; Itraconazole; Ketoconazole; Lamivudine; Mycobacterium avium-intracellulare Infection; Naphthoquinones; Nystatin; Pentamidine; Pneumocystis Infections; Pneumonia, Pneumocystis; Prednisone; Primaquine; Reverse Transcriptase Inhibitors; Stavudine; Syphilis; Toxoplasmosis; Trimetrexate; Tuberculosis; Zalcitabine; Zidovudine

Studies being conducted on opportunistic infections among people with HIV are presented in list form. The list includes new studies, those still in development, and those slated to begin in 1995. Areas of interest include candidiasis, cryptosporidiosis/microsporidiosis, cytomegalovirus (CMV), Mycobacterium avium complex (MAC) infection, Pneumocystis carinii pneumonia (PCP), toxoplasmosis, and tuberculosis (TB). Enrollment information can be obtained by calling 1-(800)-TRIALS-A (TDD 1- 800-448-0440).

Topics: AIDS-Related Opportunistic Infections; Amphotericin B; Antitubercular Agents; Atovaquone; Candidiasis; Clinical Trials as Topic; Cryptosporidiosis; Cytomegalovirus; Cytomegalovirus Infections; Ganciclovir; Humans; Immunotherapy; Mycobacterium avium-intracellulare Infection; Naphthoquinones; Paromomycin; Pneumonia, Pneumocystis; Pyrimethamine; Toxoplasmosis; Tuberculosis

The tuberculostatic activity of the herb henna (Lawsonia inermis Linn.) was tested in vitro and in vivo. On Lowenstein Jensen medium, the growth of tubercle bacilli from sputum and of Mycobacterium tuberculosis H37Rv was inhibited by 6 micrograms/ml of the herb. In vivo studies on guinea pigs and mice showed that the herb at a dose of 5 mg/kg body weight led to significant resolution of experimental tuberculosis following infection with M. tuberculosis H37Rv.

Topics: Animals; Guinea Pigs; In Vitro Techniques; Mice; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Naphthoquinones; Tuberculosis

This paper presents the results of the tuberculin-testing of over 3,600 patients in tuberculosis hospitals and of nearly 34,000 schoolchildren in widely separated areas where arrangements could be made for specially trained personnel to work with uniform materials and techniques. Both patients and children were tested with an intradermal dose of 5 TU, and the children were retested with 100 TU if the reactions were less than 5 mm.THE RESULTS CONFIRM THOSE OF EARLIER PAPERS, THAT AT LEAST TWO DIFFERENT KINDS OF NATURALLY ACQUIRED TUBERCULIN SENSITIVITY ARE FOUND IN MANY HUMAN POPULATIONS: a high-grade sensitivity, designated as specific for virulent tuberculous infection, and a low-grade kind designated as non-specific, or not specific for tuberculous infection. Specific sensitivity is the kind found in tuberculous patients and in some schoolchildren everywhere. It follows a remarkably uniform pattern wherever it is found, apparently varying only in prevalence, not in degree, from place to place. In contrast, non-specific sensitivity varies both in prevalence and in degree. It ranges from nearly universal prevalence in some localities to almost complete absence in others, from a low degree to a relatively high degree approaching that of specific sensitivity. Non-specific sensitivity is not correlated with specific sensitivity and may have different causes in different places.Serious practical problems are encountered as the prevalence and intensity of non-specific sensitivity increase, because the larger non-specific reactions cannot be distinguished from the smaller specific reactions with the tuberculin products in use today. A better, though not entirely satisfactory, separation of infected and uninfected persons might be obtained by using different criteria in different geographic areas for what is called a positive reaction to the 5 TU test. Changing the current criterion would probably provide a better estimate of the prevalence of infection in some communities: a lower proportion of the uninfected would be called positive at the expense of calling a few infected persons negative.The analogous problem of separating specific from non-specific sensitivity in cattle has been provisionally solved by the veterinarians by comparative testing with tuberculins made from different types of mycobacteria. Similar methods are now being investigated for possible application to tuberculosis control work in human populations.

Topics: Animals; Cattle; Child; Humans; Naphthoquinones; Prevalence; Rare Diseases; Tuberculin; Tuberculin Test; Tuberculosis

Topics: Antifibrinolytic Agents; Hemoptysis; Humans; Naphthoquinones; Tuberculosis; Tuberculosis, Pulmonary; Vitamin K; Vitamin K 1

Topics: Animals; Antifibrinolytic Agents; Mice; Naphthoquinones; Retinoids; Tuberculosis; Vitamin K

Topics: Naphthoquinones; Oxidation-Reduction; Tuberculosis; Tuberculosis, Pulmonary