Design, synthesis, modelling and activity of novel anti tubercular compounds

Abstract

As a paradigm chronic infectious disease, tuberculosis exhibits a variety of clin. presentations ranging from primary tuberculosis to reactivation tuberculosis. In recent years there has been a worldwide upsurge in incidence of tuberculosis esp. those caused by multi drug resistant strains of M. tuberculosis. Pyrroles are a new class of mols. that exhibit anti microbial activity. We have synthesized 500 novel compds. and tested these for activity against M. tuberculosis isolates. Several of these compds. have shown activity against M. tuberculosis. The MIC50 and MIC90 values of two compd. viz. LL3522 and LL3858 were (MIC50 0.12 &0.06 μg/mL; MIC90 0.25 &0.25 μg/mlresp.). LL3858 demonstrated dose dependent mycobactericidal activity and synergy with Rifampicin in the in vitro assays. When the mice were infected with a sub LD of M. tuberculosis and then treated with LL3858 at 12.5 mg/kg or 25 mg/kg per day for 4 wk, the log10 CFU counts in the organs of treated mice were significantly lower than the control group. Further, treatment with LL3858 for 8 and 12 wk reduced the log10 CFU counts in the target organs of treated animals and a complete absence of growth was seen in two of six mice treated with LL3858 for 12 wk. The effectiveness of LL3858 monotherapy was better than Isoniazid. Combination therapy with LL3858 plus anti-TB drugs (Isoniazid, Rifampicin, Pyrizinamide, and Ethambutol) was superior to that with LL3858 or any anti- TB drug alone. Combination treatment for eight weeks with LL3858 plus Isoniazid and Rifampicin or LL3858 plus Isoniazid, Rifampicin and Pyrizinamide sterilized the lungs and spleens of three of six and four of six mice resp. Prolonged treatment for 12 wk with LL3858 plus IR or LL3858plus IRZ sterilized the target organs in six of six mice infected with sensitive/resistant strains. The pilot Pharmacokinetics expts. of LL3858 conducted in mice and dogs indicated that the compd. is bioavailable, levels over MIC in serum for increased time and better half life and Cmax than Isoniazid. In the acute toxicity expts. in mice by oral route LL3858 showed LD50 value of 700 mg/kg. These results indicate that LL3858 is effective in in vitro and in vivo against M. tuberculosis and is also effective when given in combination.