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Tilorone dihydrochloride (1) has great potential for inducing interferon against pathogenic infection. In this paper, we describe a convenient preparation method for 2,7-dihydroxyfluoren-9-one (2), which is a usual pharmaceutical intermediate for preparing tilorone dihydrochloride (1). In the novel method, methyl esterification of 4,4'-dihydroxy-[1,1'-biphenyl]-2-carboxylic acid (4) was carried out under milder conditions with higher yield and played an important role in the preparation of compound 2. The structures of the relative intermediates and target compound were characterized by melting point, IR, MS, and ¹H-NMR. Furthermore, the synthesized tilorone dihydrochloride exhibited an obvious effect on induction of interferon-α (IFN-α) in mice within 12 h, and the peak level was observed until 24 h. This fruitful work has resulted in tilorone dihydrochloride becoming available in large-scale and wide application in clinics, which has a good pharmaceutical development prospects.

Tilorone is an interferon inducer with anticancer activity. Twenty-two novel tilorone analogs were synthesized by improvements of fluorenone skeleton, side chains and amino groups to screen new anticancer agents. In vitro evaluation showed that ten new compounds had better anticancer activities than tilorone. Among them, 2c (IC50 < 7 μM against cancer cell lines and IC50 > 35 μM against non-cancer cell lines) and 5d (IC50 < 10 μM against cancer cell lines and IC50 > 53 μM against non-cancer cell lines) exhibited the best anticancer activities and selectivities. Pharmacophore modeling of highly active compounds was carried out by Molecular Operating Environment (MOE) to generate a visualized model for compound design in future study., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Properties of interferon productivity of several inducers of interferon, analogs of amixin, have been studied in vivo. It has been shown, that under the influence of injected agents the content of endogenic interferon in the blood serum of laboratory animals increased and their non-fractionated cells of the peripheral blood (splenocites and macrophages) synthesized alpha- and gamma-interferon.

New synthetic routes to the orally active, interferon-inducing antiviral agent tilorone dihydrochloride, 2,7-bis-[(diethylamino)ethoxy]fluoren-9-one dihydrochloride (1a), were developed. The routes involved the preparation and solvolysis of tetrazonium fluoroborate salts of 2,7-diaminofluoren-9-one. Nonplanar (1b), 9-sulfone (1c), and fluorene (1d) analogues of tilorone dihydrochloride were also prepared. Compounds 1b and 1c were evaluated for interferon induction.

The synthesis and pharmacological activity of several adamantane derivatives and analogs of tilorone are described as part of a systematic research on potential antiviral compounds and/or interferon inducers.

A series of carbonyl derivatives of tilorone was synthetized by reaction with appropriate amino compounds, mainly hydrazines and hydrazides. The condensation products obtained were tested for cancerostatic activity against the murine leucaemia L 1210 and the Walker carcinosarcoma of the rat. Only three of the substances under investigation (1a, 5, 13) proved active against the Walker carcinosarcoma, one of which (5) being comparable to tilorone. No activity against L 1210 was observed, even tilorone exerted no effect. The reduction in activity against the Walker carcinosarcoma which resulted from the carbonyl substitution might be caused by a decrease in the ability to intercalate into DNA.