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The structures of all newly synthesized compounds were confirmed by1H NMR,13C NMR, IR, mass spectrometry(ESMS and HRMS) and elemental analysis (see Supporting information ). The compounds presented in this study namely alkyl 4-(alkyl/aryl carbamothioyl) piperazine-1-carbodithioate (14–38) were evaluated for anti-Trichomonas and spermicidal potential along with RT inhibitory activity by using enzymatic RT assay (Table 1). Trichomonas vaginalis causes punctuate hemorrhages giving HIV open access to its target T-lymphocytes. These hemorrhages leak the virus and cause them to concentrate in the infected area, which increase HIV transmission by 2 to 3 fold.All the synthesized compounds (14–38) except 25and 36exhibited anti- trichomonas activity ranging from 7.78–500lg/mL. Remarkable activity (better than N-9, MIC 20 lg/mL) was observed in compounds 28, 33 and 14 which were active at 7.78lg/mL, 15.56 lg/mL and 15.56 lg/mL,respectively. A potent contraceptive (spermicidal) activity in microbicides would attract users, especially those at a high risk of acquiring HIV/STD, and may improve compliance in usage. Spermicides capable of killing 100% human sperm almost instantaneously at physiological concentrations in vitro are likely to provide adequate pregnancy protection in vivo. Among synthesized twenty five compounds, thirteen compounds ( 14, 16, 18, 23, 26–31, 33, 36and 38)exhibited spermicidal activity (Table 1) at 0.025–2% (w/v) concentration and irreversibly immobilized 100% normal human spermatozoa. Out of these thirteen compounds, four compounds ( 18, 26,28and 33) were active at concentration 0.025–0.05% comparable or even more active than marketed spermicide N-9 (MEC, 0.05%).Two compounds ( 18 and 33) demonstrated extremely potent spermicidal activity at MEC 0.025%. All the compounds inhibited the RT ranging 1.90–44.67% at 100 ug/mL concentration. The compounds that showed moderate inhibitory activity (>30%) were 16, 18, 20, 29, 31, 33whereas the control NNRTIs marketed drug Nevirapine (NVP) showed 99.6% inhibition. The enzyme assay results were visualized in combination with anti-trichomonas and spermicidal activity. The results are summarized in Table 1 along with standard drug NVP. This study included 1,4-disubstituted piperazine compounds(14–38) having a substituted thiourea at the N1-position while substituted dithiocarbamates at N4-position. The thiourea substituents R1 were benzyl, phenyl, 3-pyridyl, phenethyl and benzoyl while the dithiocarbamate substituents R2 have been propyl,butyl, hexyl, octyl, and benzyl. The anti- Trichomonas activityresults suggested that the alkyl substituents at N4-carbodithioate group were preferred over benzyl substituent. The hexyl substituent at N4-position (R2) of piperazine resulted in most active compound 28 (MIC, 7.78 lg/mL) followed by propyl/octyl substitution (compounds 14 and 33, 15.56 lg/mL). On the other hand the benzoyl group at N1-thiourea substituent was most effective ( 18, 23, 28, 33 and 38). The results of spermicidal activity showed that the preference of alkyl chain at N4-carbodithioatewas octyl > hexyl > propyl > benzyl > butyl whereas benzoyl wasmost suitable group at N1-thiourea substituent. Two compounds(26and 28) were as active as N-9 (MEC, 0.05%) while two others(18and 33) exhibited two fold activity. Among twenty five newly synthesized dithiocarbamate–thiourea hybrids ( 14–38), six compounds ( 16, 18, 20, 29, 31and 33)showed 30.87–44.67% RT inhibition at 100 l g/mL. The thiourea moiety was thought responsible for RT inhibition. The activity with respect to the substituent at N1-position (R1) of piperazine was of the following order: 3-pyridyl (31, 44.67%) > benzoyl ( 33,41.29%) > benzyl ( 29, 36.46%) > phenyl ( 20, 30.87%) > phenethyl(17, 28.44%). It seems that structural combination of 3-pyridyl/benzoyl/benzyl at N1and octyl carbodithioate at N4-position was most desirable for RT inhibition. The structure of most active compounds (18and 33) suggested that benzoyl thiourea at N1and propyl/octyl carbodithioate at N4-position of piperazine were most required for sperm immobilization. The vaginal microbicidal activity comparisons of these compounds were made in view of all three activities together to achieve the aim to arrive at a pharmacophore possessing multiple activities. The study resulted in twelve dually active compounds(14, 16, 18, 23, 26-31, 33and 38) of which the most promising compound was octyl 4-(benzoylcarbamothioyl) piperazine-1-carbodithioate ( 33) as it showed anti- Trichomonas (15.56 lg/mL),spermicidal (0.025%) activity and RT inhibition (41.29%). |
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