Design and synthesis of thiazoles and their analogues as antiflaviviral & cancer chemopreventive agents

Abdelrahman Salah Mayhoub, Purdue University

Abstract

PART I: Flaviviruses are one of the most clinically important pathogens and their infection and mortality rates are increasing steadily worldwide. Moreover, the landscape infected with flaviviruses is in a continuous expansion. On the other hand, development of effective antiflaviviral agents is still a challenging field. Of the vast number of articles on the discovery and development of antiviral agents, relatively few deal with dengue, West Nile, or other flaviviruses. The hit compound DO3 phenylthiazole provided a template for the design and synthesis of antiflaviviral agents that inhibit the flaviviruses by targeting their envelope protein (E protein). The lead compound methyl 4-(dibromomethyl)-2-(4-chlorophenyl)-thiazole-5-carboxylate (1), which was obtained by structural optimization of DO3, had the most potent antiviral activity among the first- and second-generation antiflaviviral compounds. The lead compound 1 had two main drawbacks. First, it has a short plasma half-life. Second, there is a correlation between its antiflaviviral activity and the presence of the reactive and therefore potentially toxic dibromomethyl moieties at the thiazole-C4 position. A series of third-generation lead compound 1 analogues have been synthesized and tested against yellow fever virus using a cell-based assay. The compounds were designed with the objectives of improving metabolic stability, therapeutic index, and antiviral potency. First, the biological effect of C4 and C5 substitution were examined. The methylthio ester 16 and the dihydroxypropylamide 23 analogues had the best antiviral potencies and improved therapeutic indices and metabolic stabilities relative to the parent compound 1. On the other hand, replacement of the methyl ester of the lead compound 1 with heterocycles provided less active compounds. Although a great deal of effort was expended to find a safe and effective dibromomethyl isoster, none of the dibromo replacements led to a better antiviral activity than the brominated lead compound 1, with the exception of the monobromo analogue 44, which is expected to be more susceptible to endogenous nucleophilic substitution because of less steric hindrance and consequently more toxicity expected in vivo. The great advancement in this part was achieved by adding a linear hydrophobic tail para to the phenyl ring, which led to a new class of phenylthiazole antiflaviviral compounds that lack the toxic dibromomethyl moiety. This led to development of a drug-like phenylthiazole 80 that had high antiflaviviral selectivity (TI = 147) with high degree of plasma metabolic stability (plasma t1/2 8.1 h). In addition to the hit compound DO3, I tried to optimize another hit compound PO2. No significant improvements have been achieved in the case of PO2 analogues. This might be because of the higher cytotoxicity of aminoguinidinyl-containing derivatives. Part II: Chemoprevention is an approach to decrease cancer morbidity and mortality through inhibition of carcinogenesis and prevention of disease progression. Although the trans stilbene derivative resveratrol has chemopreventive properties, its action is compromised by weak non-specific effects on many biological targets. Replacement of the stilbene ethylenic bridge of resveratrol with a 1,2,4-thiadiazole heterocycle and modification of the substituents on the two aromatic rings afforded potential chemopreventive agents with enhanced potencies and selectivities when evaluated as inhibitors of aromatase and NF-κB, and as inducers of quinone reductase 1 (QR1). Aromatase is an established target not only for breast cancer chemotherapy, but also for breast cancer chemoprevention. The moderate and non-selective aromatase inhibitory activity of resveratrol (121a) was improved, to a submicromolar range, by replacement of the ethylenic bridge with a thiadiazole and the phenyl rings of 123a with pyridines (e.g. compound 123b). The aromatase inhibitory activity was further improved, to a single digit nanomolar range using a 1,3-thiazole as the central ring and modifying the substituents on "A" ring to target the Met374 residue of aromatase. On the other hand, targeting the hydroxyl group of Thr310 by a hydrogen-bond acceptor on the "B" ring did not improve in the aromatase inhibitory activity. NAD(P)H:quinone reductase 1 (QR1) exhibits its cancer protective activity mainly by preventing formation of intracellular semiquinone radicals, and by generating α-tocopherolhydroquinone, which acts as a free radical scavenger. Therefore, it is believed that QR1 inducers can act as cancer chemopreventive agents. Resveratrol (121a) requires a concentration of 21 µM to double QR1 activity (CD = 21 µM). The stilbene double bond of resveratrol was replaced with a thiadiazole ring and the phenols were eliminated to provide a more potent and selective derivative 123a (CD = 2.1 µM). Optimizing the subsitiuent pattern of the two phenyl rings and the central heterocyclic linker led to highly potent and selective QR1 inducer 148b with a CD value of 0.087 µM.

Degree

Ph.D.

Advisors

Cushman, Purdue University.

Subject Area

Pharmacology|Biochemistry

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