Synthesis of novel sulfonamide-1,2,4-triazoles, 1,3,4-thiadiazoles and 1,3,4-oxadiazoles, as potential antibacterial and antifungal agents. Biological evaluation and conformational analysis studies.

The significant antifungal activity of a series of sulfonamide-1,2,4-triazole and 1,3,4-thiazole derivatives against a series of micromycetes, compared to the commercial fungicide bifonazole has been reported. These compounds have also shown a comparable bactericidal effect to that of streptomycin and better activity than chloramphenicol against various bacteria. In view of the potential biological activity of members of the 1,2,4-triazole, 1,3,4-thiadiazole and 1,3,4-oxadiazole ring systems and in continuation of our search for bioactive molecules, we designed the synthesis of a series of novel sulfonamide-1,2,4-triazoles, -1,3,4-thiadiazoles and -1,3,4-oxadiazoles emphasizing, in particular, on the strategy of combining two chemically different but pharmacologically compatible molecules (the sulfomamide nucleus and the five member) heterocycles in one frame. Synthesized compounds were tested in vitro for antibacterial and antifungal activity and some analogues exhibited very promising results especially as antifungal agents. In order to explain structure-activity relationships, conformational analysis was performed for active and less active analogues using NMR spectroscopy and molecular modeling techniques. Furthermore, molecular properties which can be further used as descriptors for SAR studies, were predicted for the synthesized analogues. In general, antifungal activity seems to depend more on the triazol-3-thione moiety rather than the different length of the alkyl chain substitutions.

Cytogenetic and antineoplastic effects by newly synthesised steroidal alkylators in lymphocytic leukaemia P388 cells in vivo.

New compounds with potential antitumour activity were synthesised by combining nitrogen mustard with the steroidal skeleton, in an effort to improve specificity and at the same time reduce systemic toxicity. The steroidal part is aimed to serve as a biological platform enabling the alkylating moiety to approach its site of action by altering its physicochemical properties. The purpose of the present investigation was to evaluate these compounds for anti-neoplastic activity. The compounds tested have as alkylators either para-NN-bis(2-chloroethyl)-aminophenyl-butyrate (CHL) or para-N,N-bis(2-chloroethyl)-aminophenyl-acetate (PHE) esterified with a differently modified steroidal nucleus. The eight newly synthesised compounds were compared on a molar basis with respect to their ability to induce sister chromatid exchanges (SCEs) and to modify proliferation rate indices (PRI) in lymphocytic leukaemia P388 cells in mice in vivo. The life span of BDF1 mice inoculated with P388 leukaemia cells was also estimated (anti-leukaemic activity). The compounds that were effective in inducing cytogenetic effects in lymphocytic leukaemia cells in vivo were also effective in inducing antineoplastic effects in BDF1 mice inoculated with P388 leukaemia cells. These results suggest that the in vivo cytogenetic effects in conjunction with the antineoplastic activity of modified steroidal alkylators depend on the configuration of the whole molecule and on the appropriate combination of the alkylator with the steroidal molecule: a pronounced cytogenetic and anti-neoplastic action was demonstrated by the compounds that contain either PHE or CHL as alkylators and are esterified with either a steroidal nucleus that carries a cholesten group in the 17 position of the D-ring, or with a steroidal nucleus having an exocyclic NHCO-group in the D-ring. In contrast, a ketone group or an NHCO-group in the D-ring inserted endocyclically in the steroidal nucleus esterified with either CHL or PHE failed to induce cytogenetic or anti-neoplastic effects.

Activity of 17 beta-hydroxy-3-aza-A-homo-4 alpha-androsten-4-one-p-N, N-bis(2-chloroethyl)aminophenoxyacetate (NSC-620480) in P388 leukemia. Activity of steroidal lactams in Ehrlich tumor.

A new homo-aza-steroidal ester, 17 beta-hydroxy-3-aza-A-homo-4 alpha-androsten-4-one-p-N,N-bis(2-chloroethyl)aminophenoxyaceta te gives a T/C greater than 125% in the treatment of P388 lymphoid leukemia. Modified and unmodified steroids without alkylating congener have been studied for activity in L1210 leukemia and EAT cells.

Effect of an homo-aza-steroidal ester on estrogen receptor.

A new modified steroid esterified with the cytotoxic moiety, p-[N,N-bis(2-chloroethyl)amino]phenyl-acetic acid, has been synthesized and tested for interaction with estrogen receptor and cytotoxic activity on the MCF-7 cell line.

Potentiation by caffeine of cytogenetic damage induced by steroidal derivatives in human lymphocytes in vitro.

We studied the effects of three newly synthesized steroidal derivatives of nitrogen mustards, alone or in combination with caffeine, on sister chromatid exchange (SCE) frequencies and on human lymphocyte proliferation kinetics. The agents have as alkylator functionalities either P-N,N-bis(2-chloroethyl)aminophenyl-buturate (CHL) or P-N,N-bis(2-chloroethyl)aminophenyl-acetate (PHE), esterified with a modified steroidal nucleus. An enhancement of SCE frequency was seen with compounds which contain either PHE or CHL as alkylators and are esterified with a steroidal nucleus having added a cholestene group in the 17-position of the D-ring. The exocyclic insertion of an -NHCO- group in the D-ring of the steroidal nucleus esterified with PHE (amide ester of PHE) gave a compound showing increased SCE frequency. Enhanced cytogenetic damage was observed when lymphocytes were exposed in vitro to caffeine. The compounds, alone or in combination with caffeine, caused a concentration-dependent increase in SCE frequencies and cell division delays, and caffeine was found to act synergistically with the steroidal alkylators.

Further studies on the antineoplastic activity of homo-aza-steroidal esters.

The modified steroidal alkylating agents, 17 beta-hydroxy-3-aza-A-homo-4 alpha-androsten-4- one(p-[bis(2-chloroethyl)amino]phenyl)butyrate(1),3 alpha-hydroxy- 13,17-seco-5 alpha- butyrate(2),3 beta-hydroxy-13,17-seco-5-androsten-17-oic- 13,17-lactam(p-[bis-(2-chloroethyl)amino]phenyl)butyrate(3) and and (p-[bis(2-chloroethyl)amino]phenyl)butyric acid(4) have been tested against L1210, P388, Ehrlich ascites tumors (EAT), Lewis lung (LL) carcinoma and adenocarcinoma CA-755. Of four compounds evaluated in L1210 leukemia, none displayed antileukemic activity. Almost all of the four compounds were more or less active against P388 leukemia. Compound 2 possesses a slight antitumor activity in EAT, while only compound 1 appears to be active in LL carcinoma. The antitumor activity of the three modified steroidal esters on adenocarcinoma CA-755 seems to be interesting.

Synthesis of a new nor-aza-steroidal ester of p-N,N-bis-(2-chloroethyl)aminophenylbutyric acid and in vitro study of its mutagenicity and clastogenicity.

A new nor-aza-steroidal ester of chlorambucil has been synthesized. The study of the mitotic index in CHO and HeLa cells treated with this compound showed that it may be a cytostatic drug. It was also found that treatment of CHO cells with a dose as low as 5 micrograms/ml induces a large number of sister chromatid exchanges. A great number of abnormal metaphases has been observed when CHO cells were treated with the compound at a dose of 25 micrograms/ml. When the compound was tested in the Ames/Salmonella microsome assay, it was found to be mutagenic in strains TA100 and TA1535, both with and without metabolic activation.