3--hydroxy-5--(4-isobutylpiperazinyl)benzoxazinorifamycin and Leprosy

Today, the emergence of the phenomenon of drug or multidrug-resistance for community-associated diseases represents a major concern in the world. In these contexts, the chronic infectious disease, leprosy, grounded by a slow-growing bacterium called Mycobacterium leprae or Mycobacterium lepromatosis is a leadingcause of severe disfiguring skin sores and nerve damage in the arms, legs, and skin areas around the body. Even, over 200,000 new leprosy cases are being accounted every year along with the relapsed leprosy cases. Nonetheless, this has been considered a curable disease with a higher dose of multidrug therapy (MDT) for a long period of time. The prolonged action of a high dose of combination drugs administration may cause an adverse reaction that can significantly affect patient compliance, particularly the outbreak of multidrug-resistance in the infected person. To overcome these shortfalls or prevent the resistance-associated problems, researchers are diligently involved in the structural modifications of the clinically used anti-leprosy drugs or the allied compounds for the structure-antimycobacterial activity relationship study. This review article described the detailed synthesis and biological assays of different anti-leprosy compounds reported by several research groups.

Topics: Humans; Leprostatic Agents; Leprosy; Structure-Activity Relationship

In the present study, we evaluated the in vivo anti-Mycobacterium leprae activities of KRM-1648 (KRM) given at long intervals in combination with ofloxacin (OFLX), clofazimine (CFZ), and dapsone (DDS). We also examined the combined effects of two biological response modifiers (BRMs), gamma interferon (IFN-gamma) and granulocyte-macrophage colony-stimulating factor (GM-CSF), on the therapeutic efficacy of KRM. KRM exhibited potent therapeutic efficacy against M. leprae infection in mice even when given at 4-week intervals. KRM displayed increased efficacy in combination with OFLX, CFZ, and DDS (given three or six times per week) when given to mice in the multidrug combination KRM + OFLX + CFZ + DDS. The therapeutic efficacy of KRM given at 4-week intervals was increased by combined use with IFN-gamma but not by GM-CSF. Adoptive transfer of M. leprae antigen-primed lymphocytes of euthymic mice to recipient athymic nude mice with progressive M. leprae infection markedly enhanced host resistance.

Topics: Adoptive Transfer; Animals; Clofazimine; Dapsone; Drug Therapy, Combination; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Immunologic Factors; Interferon-gamma; Leprostatic Agents; Leprosy; Mice; Mice, Inbred BALB C; Mice, Nude; Ofloxacin; Rifamycins

Inhibition of the multiplication of Mycobacterium leprae in the footpads of nude mice by the oral administration of sparfloxacin, a new quinolone, and 3'-hydroxy-5'-(4-isobutyl-1-piperazinyl)benzoxazinorifamycin (KRM-1648), selected from a series of newly synthesized benzoxazinorifamycins, was studied. When the 2 drugs were administered alternately at intervals of 3 or 4 days, (i.e., each drug was administered once weekly), or simultaneously once weekly, between 3 and 5 months after inoculation of nude mice with M. leprae, 10 mg sparfloxacin and 0.6 mg KRM-1648 per kg bodyweight were sufficient to prevent multiplication of the organisms. Only partial inhibition of multiplication was achieved by alternate administration of 5 mg sparfloxacin and 0.3 mg KRM-1648 per kg, as was the case for 20 mg sparfloxacin per kg or 1 mg KRM-1648, each drug administered alone once weekly. The addition to these 2 drugs of dapsone, administered in the diet in a concentration of 0.001 g per 100 g, enhanced their effect. The potential usefulness of multidrug regimens including these compounds is considered.

Topics: Administration, Oral; Animals; Dapsone; Drug Administration Schedule; Drug Therapy, Combination; Female; Fluoroquinolones; Leprostatic Agents; Leprosy; Mice; Mice, Inbred BALB C; Mice, Nude; Mycobacterium leprae; Quinolones; Rifamycins

In this study, the in vitro and in vivo anti-Mycobacterium leprae activity of the newly developed benzoxazinorifamycin, KRM-1648, in combination with clofazimine (CFZ) or dapsone (DDS) was evaluated. In vitro anti-M. leprae activities of KRM-1648, CFZ, and DDS along with their combinations were measured by the BACTEC 460 TB System. KRM-1648 (0.01 microgram/ml), CFZ (0.5 microgram/ml), and DDS (2.0 micrograms/ml exhibited a significant anti-M. leprae activity, reducing growth index (GI) values by 78%, 30%, and 35% by day 18, respectively. Combinations of KRM-1648 with either CFZ or DDS, or both caused only a slight increase in the efficacy. BALB/c nude mice infected subcutaneously with 1 x 10(6) of M. leprae Thai-53 strain and test drugs were given to mice by gavage once daily six times per week for up to 50 days, from day 31 to day 80. Animals were observed for the growth of organisms in the hindfoot pad during the 12 months following infection. KRM-1648 given at the dose of 0.001 mg/mouse exhibited potent antileprosy activity. KRM-1648 exhibited a significant combined effect with either CFZ or DDS, or both against M. leprae infection, except that there was no significant difference in efficacy between KRM-1648 + CFZ and CFZ alone. Furthermore, the efficacy was most increased in the three-drug regimen KRM-1648 + CFZ + DDS.

Topics: Animals; Clofazimine; Dapsone; Drug Therapy, Combination; Leprostatic Agents; Leprosy; Mice; Mice, Inbred BALB C; Mice, Nude; Rifamycins

The in vivo anti-Mycobacterium leprae activity of the newly synthesized benzoxazinorifamycin, KRM-1648, was studied. KRM-1648 was given orally to athymic nude mice, infected subcutaneously with M. leprae in the hindfoot pad, at doses between 0.001 and 0.01 mg of the drug/mouse/day six times per week, from day 31 to day 80. KRM-1648 administration markedly suppressed bacterial growth in the foot pads for 360 days. KRM-1648 given daily at the dose of 0.01 mg/mouse elicited a 2-4-log decrease in the number of acid-fast bacilli. The therapeutic effects of KRM-1648 were significantly higher than that of rifampin when both drugs were given in the same dosage. Moreover, when mice were fed a KRM-1648-containing diet (0.00004%-0.0004%), the drug displayed an even higher efficacy against M. leprae infection, causing an almost 4-log decrease in the number of leprosy bacilli in the infected foot pad compared to untreated controls.

Topics: Administration, Oral; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Leprostatic Agents; Leprosy; Mice; Mice, Inbred BALB C; Mice, Nude; Mycobacterium leprae; Rifampin; Rifamycins