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Further modifications of the structural features of Schiff bases of hydroxyaminoguanidines (SB-HAG) led to nine substituted salicylaldehyde Schiff bases of HAG (SSB-HAG) derivatives and three other SB-HAG derivatives. These new compounds were tested for the first time against infection by a coronavirus, mouse hepatitis virus (MHV). The most active compound, 2 [1-[(3'-allyl-2'-hydroxybenzylidene)amino]- 3-hydroxyguanidine], against the growth of MHV is about 376 times more active than hydroxyguanidine and about 564 times more active than HAG itself when the TCID50 values are compared. Plaque assays of MHV released from cells treated with these compounds suggest that SSB-HAG tosylate may inhibit the transcription of viral RNAs in virus-infected cells. Quantitative structure-activity relationship (QSAR) analyses of two subsets show that the inhibitory activities correlate well with the electronic and the lipophilic parameters. The structural requirements for the antiviral activity of substituted SSB-HAG tosylate against coronaviral infection are stringent according to the inhibitory activities and QSAR analysis of these new compounds.

Thirty Schiff bases of hydroxysemicarbazide (Ar-CH=NNHCONHOH) have been synthesized and tested against L1210 murine leukemia cells. The IC(50) values were found to be in a range from 2.7 x 10(-6) to 9.4 x 10(-4) M. A total of 17 out of the 30 compounds had higher inhibitory activities than hydroxyurea (an anticancer drug currently used for the treatment of melanoma, leukemia, and ovarian cancer) against L1210 cells. Six compounds with IC(50) values in micromolar range were 11- to 30-fold more potent than hydroxyurea (IC(50) = 8.2 x 10(-5) M). The partition coefficient (log P) and ionization constants (pK(a)) of a model compound [1-(3-trifluoromethylbenzylidene)-4-hydroxysemicarbazide, 1] were measured by the shake-flask method, and the measured log P was used to derive Hansch-Fujita pi constant of -CH=NNHCONHOH. On the basis of the newly derived pi and those of other moieties, the partition coefficients (SlogP) of the other 29 compounds were calculated by the summation of pi values. Quantitative structure-activity relationship (QSAR) analysis showed that, besides the essential pharmacophore (-NHCONHOH), hydrophobicity (SlogP), molecular size/polarizability (calculated molar refractivity), and the presence of an oxygen-containing group at the ortho position (I) were important determinants for the antitumor activities. In conclusion, the results obtained in this study show that several Schiff bases of hydroxysemicarbazide are potent inhibitors of tumor cells and warrant further investigation as cancer chemotherapeutic agents.

Hydroxyurea, hydroxyguanidine, and some thiosemicarbazones have been shown to have anticancer and antiviral activities. One of their possible sites of action is the enzyme ribonucleotide reductase (RR). Combination of the structural features of these compounds led to the design and synthesis of the Schiff bases of N-hydroxy-N'-aminoguanidine. Synthesis and structure-activity studies of some of these compounds point to increased size and lipophilicity as important factors for activity. To optimize the activities of this series of compounds, 13 derivatives of high lipophilicity and molecular size have been synthesized and their biological activities studied. The most active anticancer compounds against L1210 in vitro (compounds 9 and 12) are about 7 times more active than hydroxyguanidine and hydroxyurea. The most active antiviral compounds against Rous sarcoma virus transformation of chick fibroblasts in vitro (7, 9) are about 40 times more active than hydroxyguanidine. One of the compounds (4) shows promising activity in vivo (% T/C = 140 against P388 leukemia in mice) and is undergoing further studies by the National Cancer Institute (NCI). Studies of the inhibition of transformation of chick embryo cells by Rous sarcoma virus show that all these compounds inhibit transformation while some compounds inhibit viral replication as well.

A series of 16 derivatives of 2-hydroxy-1H-isoindole-1,3-diones was designed and synthesized as potential antitumor agents. The cytostatic activity against L1210 cell growth of these compounds was studied, and their IC50 values were found to be in the range of 10(-4) to 10(-8) M. Quantitative structure-activity relationship analysis of these compounds showed that the inhibitory effect was well correlated with the electronic and the lipophilic parameters. Derivatives having a substituent with strongly electron-donating properties at the 6-position showed enhanced inhibitory activity while compounds having an electron-withdrawing group at the same position showed lower activity.

Hydroxyguanidine, with the imino group of guanidine and the hydroxyamino group of hydroxyurea, has functional groups believed to be important for both anticancer and antiviral activities (Adamson, R. H. Nature (London) 1972, 236,400-401). Three new N-hydroxy-N‘mninoguanidine derivatives have been synthesized and found to be 20-30 times more active than the hydroxyguanidine itself as inhibitors of ribonucleotide reductase from rat Novikoff tumors (Tai, W. A.; Lai, M. M.; Lien, E. J. “Novel -Hydroxyguanidine Derivatives as Antiviral Agents”, North American Medicinal Chemistry Symposium, University of Toronto, Toronto, Canada, June 20-24,1982; Abstr, p 144). The character of the tautomeric equilibria, the pK_a values, and the protonation sites of these hydroxyguanidine derivatives have been determined by ^(15)N NMR spectroscopy.

Hydroxyguanidine contains both features of guanidine and hydroxyurea and has antiviral and anticancer activities both in vitro and in vivo. In order to enhance the antiviral and anticancer activity of this compound, a new series of hydroxyguanidine derivatives with the following structures were synthesized: R = NNHC(= NH)NHOH, where R = aromatic or heterocyclic aldehyde. This series of compounds was prepared in order to alter the lipophilic/hydrophilic balance, as well as the electronic and steric properties of hydroxyguanidine. The anticancer activities of the compounds were tested against cultured L1210 cells. The ID50 values of the above compounds are in the range of 7.80-126 microM. They are about 10-fold more active than hydroxyurea and hydroxyguanidine. The antiviral activities were also tested by assaying the inhibition of transformation of chicken embryo fibroblasts infected with Rous sarcoma virus. The ID50 values of these new compounds are in the range of 2.76-195.2 microM. The most active ones are about 100-fold more active than hydroxyguanidine. At the ID50, no apparent toxicity to the cells was noticed.

The micelle formation tendency (log 1/CMC)) of a series of alkyldimethylbenzylammonium compounds is shown to be linearly dependent on the alky chain length, indicating no curling of the side chain up to C19. Protein binding of these charged molecules on the primary binding site for sulfaethiodole is shown to be parabolically dependent on the chain length with an optimal chain length around C16.