A pilot study of three potential vaccines for leprosy in Bombay

Three vaccines, BCG Glaxo alone (vaccine A), BCG Glaxo plus 10(7) killed Mycobacterium vaccae (vaccine B), and BCG Glaxo plus 10(7) killed M. leprae (vaccine C), were given to groups of selected children. The effects of these vaccines on subsequent quadruple skin testing 1-3 years after vaccination were compared. All three vaccines equally and significantly (p less than 0.00001) increased positivity to tuberculin, but only vaccine B was found to significantly enhance development of skin-test positivity to leprosin A (p less than 0.002). The data support the evidence previously obtained in rural Iran that the combination of BCG with killed M. vaccae is likely to be a better vaccine for leprosy than is BCG alone.     

Three years assessment of multidrug therapy in multibacillary leprosy cases

Analysis of Bacteriological Index (BI) of 584 multibacillary leprosy patients who had completed multidrug therapy (MDT) as per the recommendations of World Health Organization (WHO) and Indian Association of Leprologists (IAL) showed smear conversion rates of 56% at 24 doses and 66% at 36 doses. Taking BI as a parameter of judgement, the results indicate distinct improvement over the performance achieved through dapsone monotherapy during earlier period. IAL regimen consisting of daily initial administration of rifampicin for 21 days did not show any distinct advantage over WHO regimen. Bacteriological decline was uniformally noticeable in all patients though in cases with high initial BI, smear conversion rate was much less. All the six patients with BI more than 5, and 59 patients (70%) with BI 1 to 4.9 and 87 patients (64%) with BI 3 to 3.9 have not been rendered negative even after three years of treatment. On the contrary seventeen patients whose skin smears were still positive after receiving 24 supervised doses became bacteriologically negative subsequently, and remained so though chemotherapy was stopped. Such studies on large number of patients for a longer period is essential to establish whether chemotherapy should necessarily be continued up to the point of negativity.     

Synthesis and biological evaluation of certain 3-beta-D-ribofuranosyl-1,2,4-triazolo[4,3-b)pyridazines related to formycin prepared via ring closure of pyridazine precursors

All three amino-substituted 3-beta-D-ribofuranosyl-1,2,4-triazolo[4,3-b]pyridazines (5, 19, and 20) structurally related to formycin A were prepared and tested for their antitumor and antiviral activity in cell culture. Dehydrative coupling of 4-amino-5-chloro-3-hydrazinopyridazine (7) with 3,4,6-tri-O-benzoyl-2,5-anhydro-D-allonic acid (6) in the presence of DCC and subsequent thermal ring closure of the reaction product (8) provided 8-amino-7-chloro-3-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)- triazolo[4,3-b]pyridazine (9). Dehalogenation of 9, followed by debenzoylation, gave the formycin congener 8-amino-3-beta-D-ribofuranosyl-1,2,4- triazolo[4,3-b]pyridazine (5). Similar condensation of 5-amino-4-chloro-3-hydrazinopyridazine (13) with 6 and dehalogenation of the cyclized product (16), followed by debenzoylation, gave the isomeric 7-amino-3-beta-D-ribofuranosyl-1,2,4- triazolo[4,3-b]pyridazine (19). DCC-mediated coupling of 6 with 6-chloro-3-hydrazinopyridazine (12), followed by ammonolysis of the cyclized product (21) with liquid NH3, provided a convenient route to 6-amino-3-beta-D-ribofuranosyl-1,2,4-triazolo[4,3-b]pyridazine (20). The structural assignment of 5 was made by single-crystal X-ray diffraction analysis. Compounds 5, 19, 20, and certain deprotected nucleoside intermediates were evaluated against L1210, WI-L2, and CCRF-CEM tumor cell lines, as well as against DNA and RNA viruses in culture. These compounds did not exhibit any significant antitumor or antiviral activity in vitro.     

Synthesis and antiviral/antitumor activities of certain pyrazolo[3,4-d]pyrimidine-4(5H)-selone nucleosides and related compounds

Several pyrazolo[3,4-d]pyrimidine-4(5H)-selone ribonucleosides were prepared as potential antiparasitic agents. Treatment of 4-chloro-1-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)pyrazolo [3,4-d]pyrimidine (5a) with selenourea and subsequent deacetylation gave 1-beta-D-ribofuranosylpyrazolo[3,4-d] pyrimidine-4(5H)-selone (6a). A similar treatment of 3-bromo-4-chloro-1-(2,3,5-tri-O-benzoyl-beta-D-ribofuranosyl)pyrazolo [3,4-d]pyrimidine (5b) with selenurea, followed by debenzoylation, gave the 3-bromo derivative of 6a (6b). Glycosylation of persilylated 4-chloro-6-methyl-pyrazolo [3,4-d]pyrimidine (7) with tetra-O-acetylribofuranose (8) provided the key intermediate 4-chloro-6-methyl-1-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl) pyrazolo[3,4-d]pyrimidine (9). Ammonolysis of 9 gave 4-amino-6-methyl-1-beta-D-ribofuranosylpyrazolo[3,4-d]pyrimidine (10), whereas treatment with sodium hydroxide gave 6-methylallopurinol ribonucleoside (11a). Reaction of 9 with either thiourea or selenourea, followed by deacetylation, provided 6-methylpyrazolo[3,4-d]pyrimidine-4(5H)-thione ribonucleoside (11c) and the corresponding seleno derivative (11d), respectively. The structural assignment of these nucleosides was made on the basis of spectral studies. These compounds were tested in vitro against certain viruses and tumor cells. All the compounds except 11c exhibited significant activity against HSV-2 in vitro, whereas 11c exhibited the most potent activity against measles and has a very low toxicity. Compounds 6a, 6b, and 11d were found to be potent inhibitors of growth of L1210 and P388 leukemia in vitro.