title: Evaluation of methylthio-, methylsulfinyl-, and methylsulfonyl-analogs of alkanes and alkanoic acids as cardiac inotropic and antifungal agents.
abstract: A group of alkane and alkanoic acid compounds of general formula MeS(O)m(CH2)nR [m = 0-2; n = 1, 5, 13; R = Me, CO2H(Na)] were synthesized for evaluation as cardiac inotropic and antifungal agents. Inotropic activity was determined as the ability of the test compound to modulate in vitro guinea pig atrium contractility. The oxidation state of the S-atom was an important determinant of inotropic modulation since the thio (m = 0) analogs exhibited a positive inotropic effect. In contrast, the sulfinyl (m = 1) and sulfonyl (m = 2) analogs exhibited a negative inotropic effect. A pentyl spacer (n = 5) provided the largest positive or negative inotropic effect. The relative positive, and negative, inotropic potency orders with respect to the R-substituent were Me > or = CO2H, and CO2Na > or = Me, respectively. The most potent positive inotrope MeS(CH2)5Me (EC50 = 4.49 x 10(-6) M) could serve as a useful lead-compound for the design of a new class of positive inotropic agents. In a broad spectrum antifungal screen, the minimal inhibitory concentration (MIC) range for the five most active compounds was MeSO2(CH2)5Me (0.46-1.83 mM), MeS(CH2)13Me (0.31-1.23 mM), MeSO(CH2)13Me (< 0.009-1.87 mM), MeSO2(CH2)13Me (0.27-1.09 mM), and MeS(CH2)13CO2H (0.27-1.09 mM), relative to the reference drug Ampotericin B (< 0.0002-0.002 mM). The most active antifungal agent MeSO(CH2)13Me was selective against C. guillermondi, C. neoformans, S. cerevisiae, and A. fumigatus (strain TIMM 1776).
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Iqbal
authors.forename: C A
authors.initials: CA
authors.lastname: McEwen
authors.forename: S
authors.initials: S
authors.lastname: Sardari
authors.forename: M
authors.initials: M
authors.lastname: Daneshtalab
authors.forename: E E
authors.initials: EE
authors.lastname: Knaus
mesh_terms: D000473:Alkanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005658:Fungi / Q000187:drug effects; D006168:Guinea Pigs; D006325:Heart Atria; D066298:In Vitro Techniques; D008826:Microbial Sensitivity Tests; D009200:Myocardial Contraction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000473:Alkanes; D000935:Antifungal Agents; D002264:Carboxylic Acids; D002316:Cardiotonic Agents; D013438:Sulfhydryl Compounds