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A new type of constitutionally nonsymmetrical spirans (III), (IV), (VI), which in turn provide access to a series of 3-substituted 1,4,2-benzodithiazine 1,1-dioxide derivatives is synthesized.

Title compounds [(III) and (V)] are synthesized by condensation of sulfonamide (II) with from nitriles (I) in situ generated or directly added carbamidates (IV), respectively.

New compound (Ie) shows high activities against 13 human tumor cell lines representing lung, colon, CNS, melanoma, ovarian, renal, prostate, and breast.

Twenty four 1-[2-alkylthio-5-(azol-2 or 5-yl)-4-chlorobenzenesulfonyl]-3-hydroxyguanidines 6a-x have been synthesized in order to evaluate their biological activity. Compounds 6a, 6c, 6d, 6f, 6g, 6i-p, 6r-t, and 6v-x were tested for their in vitro anticancer activity at the US National Cancer Institute. The highest in vitro anticancer activity was found for compounds 6d, 6g and 6k with GI(50) average value in the range 1.62-1.86 μM, and TGI mean values 3.72-4.47 μM, whereas the remaining compounds showed broad spectrum of anticancer activity at low micromolar GI(50) level against all tested cancer cell lines. These results were subjected to CoMSIA analysis to establish quantitative structure-activity relationships. The results evidence that potency of these compounds correlates mainly with hydrophobic and polar surface properties of substituents located both at 2 and 5 positions of 1-(4-chlorobenzenesulfonyl) moiety of investigated 3-hydroxyguanidine series.

10 Title compounds of type (IX) are prepared and evaluated for their in vitro activities against the full NCI-60 cell line panel.

A new amination method by treating substituted aromatic or heteroaromatic chlorides with formamides is developed.

The pyridine-derived sulfonamides (amines, ethers, hydrazines and sulfides) are investigated as inhibitors of five isoforms of zinc enzyme carbonic anhydrase.

A series of novel 3-aroyl-2,3-dihydro-1,1-dioxo-1,4,2-benzodithiazines 15 – 28 as potential HIV-1 integrase (IN) inhibitors have been synthesized by the reduction of 3-aroyl-1,1-dioxo-1,4,2-benzodithiazines 1 – 14 with benzenesulfonyl hydrazide. All the compounds 15 – 28 inhibited IN mediated strand transfer reaction with IC 50 values ranging from 3 to 30 μM. The 3-(4-bromobenzoyl)-6-chloro-7-methyl-2,3-dihydro-1,1-dioxo-1,4,2-benzodithiazine 17 with the IC 50 values of 4 ± 1 and 3 ± 1 μM for 3′-processing and strand transfer, respectively, was the most potent. Compound 17 as well its analogues were 5–20-fold less potent in Y99S and H114A mutants, implicating these residues as potential drug-binding site. This is a first report implicating Y99S and H114A of IN core domain in drug-binding interactions.

Novel 3-amino-2-(4-chloro-2-mercaptobenzenesulfonyl)guanidine derivatives have been synthesized as potential anticancer agents. The in vitro antitumor activity of these compounds has been evaluated in the US National Cancer Institute (NCI), and relationships between structure and antitumor activity are discussed. The prominent compound was 1-allyl-2-[4-chloro-5-(4-chlorophenylcarbamoyl)-2-methylthiobenzenesulfonyl]-3-(5-nitrofurfurylideneamino)guanidine ( 8 ) with remarkable activity against 21 human tumor cell lines representing leukemia, lung, colon, melanoma, ovarian, renal, prostate and breast (GI 50 = 0.3–3.0 μM), and selectivity toward leukemia RPMI-8226 cell line (GI 50 = 0.3 μM, TGI = 1.4 μM).

The reaction of 3-amino-2-(2-alkylthio-4-chlorobenzenesulfonyl)guanidines 2a-j with 1,2-dicarbonyl compounds are described. Depending on structure of 1,2-dicarbonyl reagent novel 2-alkylthio-5-chloro-N-(1,2,4-triazin-3-yl)benzenesulfonamides 3-15, 1-(2-alkylthio-4-chlorobenzenesulfonyl)-3-(2-oxobutane-3-ylidenoimino)guanidines 16-18 and 2-alkylthio-4-chloro-N-(1,2-dihydroxycyclobuta[e]1,2,4-triazin-3-yl)benzenesulfonamides 19-21 are obtained. The structures of these compounds were confirmed on the basis of elemental analysis, spectral data and X-ray analysis. The compounds 4, 5, 7, 9, 10, 12-15, 17, 18 and 20 were screened at the National Cancer Institute (NCI) for their in vitro activities against a panel of 56 tumor cell lines and relationship between structure and antitumor activity are discussed. The compounds 10, 12, 17 and 20 were inactive, whereas the other compounds exhibited reasonable activity against one or more human tumor cell lines. The prominent compound 18 showed significant activity against cell lines of colon cancer (HCT-116), renal cancer (786-0) and melanoma (M14) (GI50 in the range 0.33-1.08 microM) as well as good selectivity toward non-small cell lung cancer (HOP-62) cells (GI50 = 0.05 microM, TGI = 0.38 microM and LC50 = 4.83 microM).

The syntheses of new 3-arylideneamino-1-(2-alkythio-4-chloro-5-methylbenzenesul-fonyl)guanidines 2-8 and 1-arylidene-2-(2-alkylthio-4-chloro-5-R 3 -benzenesulfonyl)-3-methylaminoguanidines 9-16 are described. The in vitro antitumor screening of compounds 2, 3, 9 and 10 was evaluated at the Institute of Pharmacy, University of Greifswald. The remaining compounds 5, 11-14 and 16 were screened at the National Cancer Institute (NCI) for their activities against a panel of 55 human tumor cell lines, and relationships between structure and anticancer activity in vitro are discussed. The highest anticancer activity was found for 2-(2-benzylthio-4-chloro-5-methylbenze-nesulfonyl)-3-methylamino-1-(5-nitrothienylidene)guanidine (12) (GI 5 0 in the range 0.3-0.6 μM), while other compounds exhibit reasonable (16) or moderate (9, 13) anticancer activities.