Role of disulfide linkage in action of bis(dialkylaminethiocarbonyl)disulfides as potent double-Edged microbicidal spermicide: Design, synthesis and biology.

Trichomoniasis and candidiasis are amongst the most common morbidity-causing reproductive tract infections, generally treated by Metronidazole and Fluconazole respectively. Poor vaginal efficacy, drug-resistance and non-spermicidal nature limit their use as topical microbicidal contraceptives. Bis(dialkylaminethiocarbonyl)disulfides (4-38) were designed as dually active, non-surfactant molecules capable of eliminating Trichomonas vaginalis and Candida strains as well as irreversibly immobilizing 100% human sperm instantly, at doses non-cytotoxic to human cervical epithelial cells and vaginal microflora in vitro. Compounds 12, 16, 17 were fifty times more active than nonoxynol-9, OTC vaginal spermicide, and compounds 12 and 17 have shown remarkable in vivo activity in rabbit model. Most promising compound 17 has shown promise for further development as a double-edged vaginal microbicide due to their improved activity and safety along with notable in vivo trichomonicidal activity. Role of disulfide group was established by loss of spermicidal activity on chemical modifications (39-56). These disulfides might be targeting thiol groups present over cell membrane of human sperm and Trichomonas as shown by fluorescence labeling of free thiols.

Azole-carbodithioate hybrids as vaginal anti-Candida contraceptive agents: design, synthesis and docking studies.

Azole and carbodithioate hybrids were synthesized as alkyl 1H-azole-1-carbodithioates (7-27) and evaluated for spermicidal/microbicidal activities against human sperm, Trichomonas vaginalis and Candida species. Seventeen compounds (7-14, 16-18 and 20-25) showed spermicidal activity at MEC 1.0% (w/v) and permanently immobilized 100% normal human spermatozoa within ∼30 s. Seventeen compounds (7-11, 13-18 and 20-25) exhibited anti-Candida activity (IC50 1.26-47.69 µg/mL). All compounds were devoid of bactericidal activity against four bacterial strains (50.00 µg/mL) and antiprotozoal activity against Trichomonas vaginalis (200.00 µg/mL). Four promising compounds (10, 17, 20 and 22) have better safety profile as compared to Nonoxynol-9 (N-9). Docking study was done to visualize the possible interaction of designed scaffold with prospective receptor (Cyp51) of Candida albicans.

Synthesis and 2D QSAR of O-sulphonated ß-aminols derivatives as novel antifungal and antibacterial agents.

Synthesis of a series of ß-aminol derivatives using regioselective opening reaction catalyzed by SiO(2) (60-120mesh) and O-sulphonation in THF-KOH system, comprising tert-butoxycarbonyl at secondary nitrogen and evaluate for various stains of bacteria and fungi. SAR study of synthesized compound using backward regression analysis.

Design and synthesis of 3-(azol-1-yl)phenylpropanes as microbicidal spermicides for prophylactic contraception.

We designed a series of 25 3-(azol-1-yl)phenylpropanes which yielded 10 compounds (3, 4, 7, 8, 13, 14, 19, 21, 23, 26) that irreversibly immobilized 100% human sperm at 1% (w/v) concentration in 60s; 12 compounds (8, 9, 15, 16, 19-21, 23-25, 27, 28) that showed potent microbicidal activity at 12.5-50 µg/mL against Trichomonas vaginalis; and 17 compounds (3-11, 13, 15, 19, 21, 23, 26, 28, 30) that exhibited potent anticandida activity with minimum inhibitory concentration (MIC) of 12.5-50 µg/mL. Almost all the compounds exhibited high level of safety towards normal vaginal flora (Lactobacillus) and human cervical (HeLa) cells in comparison to the marketed spermicide nonoxynol-9 (N-9). All the biological activities were evaluated in vitro. Two compounds (4, 8) with good safety profile exhibited multiple (spermicidal, antitrichomonas and anticandida) activities, warranting further lead optimization for furnishing a prophylactic vaginal contraceptive.