Substituted Indoloquinolines as New Antifungal Agents Seth Y. Ablordeppey, a, * Pingchen Fan, a Shouming Li, a Alice M. Clark b and Charles D. Hufford b a Florida A&M University, College of Pharmacy and Pharmaceutical Sciences, Tallahassee, FL 32307, USA b The National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, and Department of Pharmacognosy, The School of Pharmacy, University of Mississippi, University, MS 38677, USA Received 20 September 2001; accepted 8 November 2001 Abstract—Cryptolepine (2) possesses desirable properties to serve as a lead in developing new antifungal agents. Using SAR tech- niques, several analogues of cryptolepine were designed to increase potency and to broaden the antifungal spectrum over several opportunistic microorganisms. A number of 2-substituted indoloquinolines have been synthesized and evaluated in antifungal screens and several have been shown to increase potency and expand the antifungal spectrum of cryptolepine. Comparison of MICs of a number of these analogues with standard antifungal agents, shows them to be comparable to Amphotericin B and Ketocona- zole. # 2002 Elsevier Science Ltd. All rights reserved. Although the AIDS epidemic appears to have stabilized in the developed countries, there is continuing interest in new antifungal agents partially because of the chronic nature of the disease and the continuing dramatic rise in AIDS cases in the developing countries. 1 In sub- Saharan Africa, for example, it is estimated that 25.3 million people were living with AIDS by the close of last year. There are several additional reasons, 2 such as, toxicity and the emergence of fungi resistant to currently available antifungal agents that has kept the need to develop new agents at the forefront of current research. The indoloquinoline alkaloid, Cryptolepine (2) and its analogues have been the subject of several recent pub- lications. 36 Although Cryptolepine (isolated from Cryptolepis sanguinolenta) 7 has been shown to have antibacterial, 8 antihypertensive, 9 anti-aggregatory, 10 anticancer, 4,11 and other properties, it was only more recently that we have documented its antifungal activ- ity. 12 As part of a SAR study, we have shown that, N-5 alkylation of the tetracyclic structure, quindoline, 1, is essential for antifungal activity 13 and o-cycloalkylpentyl substituents on the N-5 atom has a broad-spectrum inhibition of several opportunistic infections. 14 Appar- ently, the tetracyclic structure of cryptolepine is not necessary for its antifungal activity and this has led us to propose the d-carboline moiety as a pharmacophore for antifungal activity. 14 Cryptolepine has interesting prop- erties to serve as a lead compound in antifungal drug development. For example, its zone of inhibition against Candida albicans, Cryptococcus neoformans Aspergillus niger are wider than those of Amphotericin B in agar well assays, it is fairly water soluble (  1.2 mg/mL), it has relatively low toxicity 15 and a broad spectrum of activity against opportunistic fungal and bacterial infections associated with AIDS. 16 The purpose of this study was to investigate the ability of substituents on the tetracyclic moiety to extend the antifungal spectrum and increase potency. 0968-0896/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved. PII: S0968-0896(01)00401-1 Bioorganic & Medicinal Chemistry 10 (2002) 1337–1346 *Corresponding author. Tel.: +1-850-599-3834; fax: +1-850-599- 3934; e-mail: seth.ablordeppey@famu.edu